CDKN2A/B homozygous deletion is associated with early recurrence in meningiomas
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - July 8, 2020 Category: Neurology Source Type: research

Insulin-like growth factor 2 (IGF2) protects against Huntington ’s disease through the extracellular disposal of protein aggregates
This study identifies IGF2 as a relevant factor deregulated in HD, operating as a d isease modifier that buffers the accumulation of abnormal protein species. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - July 8, 2020 Category: Neurology Source Type: research

Microvascular injury and hypoxic damage: emerging neuropathological signatures in COVID-19
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - July 8, 2020 Category: Neurology Source Type: research

Correction to: Somatic mutations in neurons during aging and neurodegeneration
In the original article, the panels “Brain organoids” and “Transgenics” were included in Fig. 5 without permission. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - July 6, 2020 Category: Neurology Source Type: research

Vesicle trafficking and lipid metabolism in synucleinopathy
AbstractThe neuronal protein α-synuclein (αS) is central to the pathogenesis of Parkinson’s disease and other progressive brain diseases such as Lewy body dementia and multiple system atrophy. These diseases, collectively referred to as ‘synucleinopathies’, have long been considered purely proteinopathies: diseases char acterized by the misfolding of a protein into small and large aggregates mainly consisting of that protein (in this case: α-synuclein). However, recent morphological insights into Lewy bodies, the hallmark neuropathology of human synucleinopathies, suggests these lesions ...
Source: Acta Neuropathologica - June 30, 2020 Category: Neurology Source Type: research

Large-scale pathway specific polygenic risk and transcriptomic community network analysis identifies novel functional pathways in Parkinson disease
Abstract Polygenic inheritance plays a central role in Parkinson disease (PD). A priority in elucidating PD etiology lies in defining the biological basis of genetic risk. Unraveling how risk leads to disruption will yield disease-modifying therapeutic targets that may be effective. Here, we utilized a high-throughput and hypothesis-free approach to determine biological processes underlying PD using the largest currently available cohorts of genetic and gene expression data from International Parkinson ’s Disease Genetics Consortium (IPDGC) and the Accelerating Medicines Partnership-Parkinson’s disease initiati...
Source: Acta Neuropathologica - June 29, 2020 Category: Neurology Source Type: research

ETMR: a tumor entity in its infancy
AbstractEmbryonal tumor with Multilayered Rosettes (ETMR) is a relatively rare but typically deadly type of brain tumor that occurs mostly in infants. Since the discovery of the characteristic chromosome 19 miRNA cluster (C19MC) amplification a decade ago, the methods for diagnosing this entity have improved and many new insights in the molecular landscape of ETMRs have been acquired. All ETMRs, despite their highly heterogeneous histology, are characterized by specific high expression of the RNA-binding protein LIN28A, which is, therefore, often used as a diagnostic marker for these tumors. ETMRs have few recurrent geneti...
Source: Acta Neuropathologica - June 29, 2020 Category: Neurology Source Type: research

H3K27M-mutant diffuse midline glioma with extensive intratumoral microthrombi in a young adult with COVID-19-associated coagulopathy
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - June 29, 2020 Category: Neurology Source Type: research

SFPQ and Tau: critical factors contributing to rapid progression of Alzheimer ’s disease
AbstractDysfunctional RNA-binding proteins (RBPs) have been implicated in several neurodegenerative disorders. Recently, this paradigm of RBPs has been extended to pathophysiology of Alzheimer ’s disease (AD). Here, we identified disease subtype specific variations in the RNA-binding proteome (RBPome) of sporadic AD (spAD), rapidly progressive AD (rpAD), and sporadic Creutzfeldt Jakob disease (sCJD), as well as control cases using RNA pull-down assay in combination with proteomics. We s how that one of these identified proteins, splicing factor proline and glutamine rich (SFPQ), is downregulated in the post-mortem br...
Source: Acta Neuropathologica - June 23, 2020 Category: Neurology Source Type: research

Enhanced axonal response of mitochondria to demyelination offers neuroprotection: implications for multiple sclerosis
AbstractAxonal loss is the key pathological substrate of neurological disability in demyelinating disorders, including multiple sclerosis (MS). However, the consequences of demyelination on neuronal and axonal biology are poorly understood. The abundance of mitochondria in demyelinated axons in MS raises the possibility that increased mitochondrial content serves as a compensatory response to demyelination. Here, we show that upon demyelination mitochondria move from the neuronal cell body to the demyelinated axon, increasing axonal mitochondrial content, which we term the axonal response of mitochondria to demyelination (...
Source: Acta Neuropathologica - June 22, 2020 Category: Neurology Source Type: research

The KBTBD6/7-DRD2 axis regulates pituitary adenoma sensitivity to dopamine agonist treatment
In this study, we first demonstrated that DRD2 underwent proteasome-mediated degradation. We further employed the yeast two-hybrid system and identified kelch repeat and BTB (POZ) domain containing 7 (KBTBD7), a substrate adaptor for the CUL3-RING ubiquitin (Ub) ligase complex, as a DRD2-interacting protein. KBTBD6/7 directly interacted with, and ubiquitinated DRD2 at five ubiquitination sites (K221, K226, K241, K251, and K258). CAB, a high-affinity DRD2 agonist, induced DRD2 internalization, and cytoplasmic DRD2 was degraded via ubiquitination under the control of KBTBD6/7, the activity of which attenuated CAB-mediated in...
Source: Acta Neuropathologica - June 22, 2020 Category: Neurology Source Type: research

Congenic expression of poly-GA but not poly-PR in mice triggers selective neuron loss and interferon responses found in C9orf72 ALS
AbstractExpansion of a (G4C2)n repeat inC9orf72 causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the link of the five repeat-encoded dipeptide repeat (DPR) proteins to neuroinflammation, TDP-43 pathology, and neurodegeneration is unclear. Poly-PR is most toxic in vitro, but poly-GA is far more abundant in patients. To directly compare these in vivo, we created congenic poly-GA and poly-PR mice. 40% of poly-PR mice were affected with ataxia and seizures, requiring euthanasia by 6  weeks of age. The remaining poly-PR mice were asymptomatic at 14 months of age, likely due to an 80% r...
Source: Acta Neuropathologica - June 19, 2020 Category: Neurology Source Type: research

Correction to: Comparative multidimensional molecular analyses of pediatric diffuse intrinsic pontine glioma reveals distinct molecular subtypes
The original version of this article unfortunately contained a mistake. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - June 19, 2020 Category: Neurology Source Type: research

Correction to: Ultrasensitive RT-QuIC assay with high sensitivity and specificity for Lewy body-associated synucleinopathies
he article Ultrasensitive RT ‑QuIC assay with high sensitivity and specificity for Lewy body‑ (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - June 17, 2020 Category: Neurology Source Type: research

ATP10B and the risk for Parkinson ’s disease
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - June 15, 2020 Category: Neurology Source Type: research

Reply: ATP10B and the risk for Parkinson ’s disease
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - June 15, 2020 Category: Neurology Source Type: research

Prion propagation estimated from brain diffusion MRI is subtype dependent in sporadic Creutzfeldt –Jakob disease
This study was designed to identify, in vivo and for the first time, subtype-dependent epicentre and lesion propagation in the brain using diffusion-weighted images (DWI), in the largest known cross-sectional dataset of autopsy-prove n subjects with sCJD. We estimate lesion propagation by cross-sectional DWI using event-based modelling, a well-established data-driven technique. DWI abnormalities of 594 autopsy-diagnosed subjects (448 patients with sCJD) were scored in 12 brain regions by 1 neuroradiologist blind to the diagnosis . We used the event-based model to reconstruct sequential orderings of lesion propagation in ea...
Source: Acta Neuropathologica - June 13, 2020 Category: Neurology Source Type: research

HIF-1 α is involved in blood–brain barrier dysfunction and paracellular migration of bacteria in pneumococcal meningitis
AbstractBacterial meningitis is a deadly disease most commonly caused byStreptococcus pneumoniae, leading to severe neurological sequelae including cerebral edema, seizures, stroke, and mortality when untreated. Meningitis is initiated by the transfer ofS. pneumoniae from blood to the brain across the blood –cerebrospinal fluid barrier or the blood–brain barrier (BBB). The underlying mechanisms are still poorly understood. Current treatment strategies include adjuvant dexamethasone for inflammation and cerebral edema, followed by antibiotics. The success of dexamethasone is however inconclusive, ne cessitating ...
Source: Acta Neuropathologica - June 11, 2020 Category: Neurology Source Type: research

Patient-derived orthotopic xenografts of pediatric brain tumors: a St. Jude resource
Abstract Pediatric brain tumors are the leading cause of cancer-related death in children. Patient-derived orthotopic xenografts (PDOX) of childhood brain tumors have recently emerged as a biologically faithful vehicle for testing novel and more effective therapies. Herein, we provide the histopathological and molecular analysis of 37 novel PDOX models generated from pediatric brain tumor patients treated at St. Jude Children ’s Research Hospital. Using a combination of histopathology, whole-genome and whole-exome sequencing, RNA-sequencing, and DNA methylation arrays, we demonstrate the overall fidelity and inter-...
Source: Acta Neuropathologica - June 10, 2020 Category: Neurology Source Type: research

CDKN2A deletion in supratentorial ependymoma with RELA alteration indicates a dismal prognosis: a retrospective analysis of the HIT ependymoma trial cohort
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - June 8, 2020 Category: Neurology Source Type: research

An optimized workflow to improve reliability of detection of KIAA1549:BRAF fusions from RNA sequencing data
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 31, 2020 Category: Neurology Source Type: research

Multiomic elucidation of a coding 99-mer repeat-expansion skeletal muscle disease
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 25, 2020 Category: Neurology Source Type: research

Neuropathology of COVID-19: a spectrum of vascular and acute disseminated encephalomyelitis (ADEM)-like pathology
We report the neuropathological findings of a patient who died from complications of COVID-19. The decedent was initially hospitalized for surgical management of underlying coronary artery disease. He developed post-operative complications and was evaluated with chest imaging studies. The chest computed tomography (CT) imaging results were indicative of COVID-19 and he was subsequently tested for SARS-CoV-2, which was positive. His condition worsened and he died after more than 2  weeks of hospitalization and aggressive treatment. The autopsy revealed a range of neuropathological lesions, with features resembling both...
Source: Acta Neuropathologica - May 24, 2020 Category: Neurology Source Type: research

Spatial enrichment of cellular states in glioblastoma
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 24, 2020 Category: Neurology Source Type: research

Evidence of distinct α-synuclein strains underlying disease heterogeneity
AbstractSynucleinopathies are a group of neurodegenerative disorders caused by the misfolding and self-templating of the protein α-synuclein, or the formation of α-synuclein prions. Each disorder differs by age of onset, presenting clinical symptoms, α-synuclein inclusion morphology, and neuropathological distribution. Explaining this disease-specific variability, the strain hypothesis postulates that each prion disease is encoded by a distinct conformation of the misfolded protein, and therefore, each synucleinopathy is caused by a unique α-synuclein structure. This review discusses the current dat...
Source: Acta Neuropathologica - May 21, 2020 Category: Neurology Source Type: research

Frequent inactivating mutations of the PBAF complex gene PBRM1 in meningioma with papillary features
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 13, 2020 Category: Neurology Source Type: research

Distribution patterns of tau pathology in progressive supranuclear palsy
AbstractProgressive supranuclear palsy (PSP) is a 4R-tauopathy predominated by subcortical pathology in neurons, astrocytes, and oligodendroglia associated with various clinical phenotypes. In the present international study, we addressed the question of whether or not sequential distribution patterns can be recognized for PSP pathology. We evaluated heat maps and distribution patterns of neuronal, astroglial, and oligodendroglial tau pathologies and their combinations in different clinical subtypes of PSP in postmortem brains. We used conditional probability and logistic regression to model the sequential distribution of ...
Source: Acta Neuropathologica - May 7, 2020 Category: Neurology Source Type: research

Histological features of gadolinium deposition in the brain, a case report
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - April 30, 2020 Category: Neurology Source Type: research

The structural differences between patient-derived α-synuclein strains dictate characteristics of Parkinson’s disease, multiple system atrophy and dementia with Lewy bodies
We report that MSA strains show several similarities with PD strains, but are significantly more potent in inducing motor deficits, nigrostriatal neurodegeneration, αSYN pathology, spreading, and inflammation, reflecting the aggressive nature of this dis ease. In contrast, DLB strains display no or only very modest neuropathological features under our experimental conditions. Collectively, our data demonstrate a specific signature for PD, MSA, and DLB-derived strains that differs from previously described recombinant strains, with MSA strains provok ing the most aggressive phenotype and more similarities with PD comp...
Source: Acta Neuropathologica - April 30, 2020 Category: Neurology Source Type: research

Ultrasensitive RT-QuIC assay with high sensitivity and specificity for Lewy body-associated synucleinopathies
In conclusion, α-synuclein RT-QuIC provides an accurate marker of synucleinopathies linked to LB pa thology and may have a pivotal role in the early discrimination and management of affected patients. The finding of no α-synuclein seeding activity in MSA seems to support the current view that MSA and LBD are associated with different conformational strains of α-synuclein. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - April 27, 2020 Category: Neurology Source Type: research

Biological sex and DNA repair deficiency drive Alzheimer ’s disease via systemic metabolic remodeling and brain mitochondrial dysfunction
AbstractAlzheimer ’s disease (AD) is an incurable neurodegenerative disease that is more prevalent in women. The increased risk of AD in women is not well understood. It is well established that there are sex differences in metabolism and that metabolic alterations are an early component of AD. We utilized a cross- species approach to evaluate conserved metabolic alterations in the serum and brain of human AD subjects, two AD mouse models, a human cell line, and twoCaenorhabditis elegans AD strains. We found a mitochondrial complex I-specific impairment in cortical synaptic brain mitochondria in female, but not male,...
Source: Acta Neuropathologica - April 24, 2020 Category: Neurology Source Type: research

MEF2 impairment underlies skeletal muscle atrophy in polyglutamine disease
AbstractPolyglutamine (polyQ) tract expansion leads to proteotoxic misfolding and drives a family of nine diseases. We study spinal and bulbar muscular atrophy (SBMA), a progressive degenerative disorder of the neuromuscular system caused by the polyQ androgen receptor (AR). Using a knock-in mouse model of SBMA, AR113Q mice, we show that E3 ubiquitin ligases which are a hallmark of the canonical muscle atrophy machinery are not induced in AR113Q muscle. Similarly, we find no evidence to suggest dysfunction of signaling pathways that trigger muscle hypertrophy or impairment of the muscle stem cell niche. Instead, we find th...
Source: Acta Neuropathologica - April 18, 2020 Category: Neurology Source Type: research

Pediatric bithalamic gliomas have a distinct epigenetic signature and frequent EGFR exon 20 insertions resulting in potential sensitivity to targeted kinase inhibition
This study identifies a promising genomically-tailored therapeutic strategy for bithalamic gliomas, a lethal and genetically distinct brain tumor of childhood. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - April 17, 2020 Category: Neurology Source Type: research

CRISPR deletion of the C9ORF72 promoter in ALS/FTD patient motor neurons abolishes production of dipeptide repeat proteins and rescues neurodegeneration
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - April 7, 2020 Category: Neurology Source Type: research

Intracellular calcium leak as a therapeutic target for RYR1 -related myopathies
This study provides the rationale for a clinical trial testing Rycals inRYR1-RM affected individuals and introduces a predictive tool for investigating the pathogenicity ofRYR1 variants of uncertain significance. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 31, 2020 Category: Neurology Source Type: research

PTEN activation contributes to neuronal and synaptic engulfment by microglia in tauopathy
AbstractPhosphatase and tensin homolog (PTEN) regulates synaptic density in development; however, whether PTEN also regulates synapse loss in a neurodegenerative disorder such as frontotemporal lobar degeneration with Tau deposition (FTLD-Tau) has not been explored. Here, we found that pathological Tau promotes early activation of PTEN, which precedes apoptotic caspase-3 cleavage in the rTg4510 mouse model of FTLD-Tau. We further demonstrate increased synaptic and neuronal exposure of the apoptotic signal phosphatidylserine that tags neuronal structures for microglial uptake, thereby linking PTEN activation to synaptic and...
Source: Acta Neuropathologica - March 31, 2020 Category: Neurology Source Type: research

Prevalence in Britain of abnormal prion protein in human appendices before and after exposure to the cattle BSE epizootic
AbstractWidespread dietary exposure of the population of Britain to bovine spongiform encephalopathy (BSE) prions in the 1980s and 1990s led to the emergence of variant Creutzfeldt-Jakob Disease (vCJD) in humans. Two previous appendectomy sample surveys (Appendix-1 and -2) estimated the prevalence of abnormal prion protein (PrP) in the British population exposed to BSE to be 237 per million and 493 per million, respectively. The Appendix-3 survey was recommended to measure the prevalence of abnormal PrP in population groups thought to have been unexposed to BSE. Immunohistochemistry for abnormal PrP was performed on 29,516...
Source: Acta Neuropathologica - March 30, 2020 Category: Neurology Source Type: research

Diverse, evolving conformer populations drive distinct phenotypes in frontotemporal lobar degeneration caused by the same MAPT -P301L mutation
AbstractTau protein accumulation is a common denominator of major dementias, but this process is inhomogeneous, even when triggered by the same germline mutation. We considered stochastic misfolding of human tau conformers followed by templated conversion of native monomers as an underlying mechanism and derived sensitive conformational assays to test this concept. Assessments of brains from aged TgTauP301L transgenic mice revealed a prodromal state and three distinct signatures for misfolded tau. Frontotemporal lobar degeneration (FTLD)-MAPT-P301L patients with different clinical phenotypes also displayed three signatures...
Source: Acta Neuropathologica - March 26, 2020 Category: Neurology Source Type: research

Correction to: Niacin-mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system
The article Niacin ‑mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system, written by Khalil S. Rawji, Adam M.H. Young, Tanay Ghosh, Nathan J. Michaels, Reza Mirzaei, Janson Kappen, Kathleen L. Kolehmainen, Nima Alaeiilkhchi, Brian Lozinski, Manoj K. Mishra, Annie P u, Weiwen Tang, Salma Zein, Deepak K. Kaushik, Michael B. Keough, Jason R. Plemel, Fiona Calvert, Andrew J. Knights, Daniel J. Gaffney, Wolfram Tetzlaff, Robin J. M. Franklin and V. Wee Yong, was originally published electronically on the publisher’s internet. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 24, 2020 Category: Neurology Source Type: research

Histone H3 wild-type DIPG/DMG overexpressing EZHIP extend the spectrum diffuse midline gliomas with PRC2 inhibition beyond H3-K27M mutation
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 19, 2020 Category: Neurology Source Type: research

Genome-wide DNA methylation profiles distinguish silent from non-silent ACTH adenomas
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 17, 2020 Category: Neurology Source Type: research

Mutated ATP10B increases Parkinson ’s disease risk by compromising lysosomal glucosylceramide export
AbstractParkinson ’s disease (PD) is a progressive neurodegenerative brain disease presenting with a variety of motor and non-motor symptoms, loss of midbrain dopaminergic neurons in the substantia nigra pars compacta and the occurrence of α-synuclein-positive Lewy bodies in surviving neurons. Here, we performed w hole exome sequencing in 52 early-onset PD patients and identified 3 carriers of compound heterozygous mutations in the ATP10B P4-type ATPase gene. Genetic screening of a Belgian PD and dementia with Lewy bodies (DLB) cohort identified 4 additional compound heterozygous mutation carriers (6/617 PD p a...
Source: Acta Neuropathologica - March 14, 2020 Category: Neurology Source Type: research

Correction to: Overlapping genetic architecture between Parkinson disease and melanoma
The original version of this article unfortunately contained a mistake. Supplementary Tables  3 and 4 are not available with the rest of the supplementary material available online. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 14, 2020 Category: Neurology Source Type: research

Concomitant 1p/19q co-deletion and IDH1/2 , ATRX , and TP53 mutations within a single clone of “dual-genotype” IDH-mutant infiltrating gliomas
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 13, 2020 Category: Neurology Source Type: research

PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment
AbstractA rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer ’s disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau181, total tau, and A β1-42 was assessed in 1261 MCI patients. We found that MCI patients who ...
Source: Acta Neuropathologica - March 12, 2020 Category: Neurology Source Type: research

Complement deposition at the neuromuscular junction in seronegative myasthenia gravis
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 10, 2020 Category: Neurology Source Type: research

Gliomas arising in the setting of Li-Fraumeni syndrome stratify into two molecular subgroups with divergent clinicopathologic features
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 10, 2020 Category: Neurology Source Type: research

DNA methylation age acceleration is associated with ALS age of onset and survival
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 7, 2020 Category: Neurology Source Type: research

Pineoblastoma is uniquely tolerant of mutually exclusive loss of DICER1 , DROSHA or DGCR8
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 2, 2020 Category: Neurology Source Type: research

rs4147929 variant minor allele increases ABCA7 gene expression and ABCA7 shows increased gene expression in Alzheimer ’s disease patients compared with controls
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - February 29, 2020 Category: Neurology Source Type: research