Neuroglial stem cell-derived inflammatory pseudotumor (n-SCIPT): clinicopathologic characterization of a novel lesion of the lumbosacral spinal cord and nerve roots following intrathecal allogeneic stem cell intervention
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - October 27, 2019 Category: Neurology Source Type: research

Poly-glycine –alanine exacerbates C9orf72 repeat expansion-mediated DNA damage via sequestration of phosphorylated ATM and loss of nuclear hnRNPA3
AbstractRepeat expansion inC9orf72 causes amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Expanded sense and antisense repeat RNA transcripts inC9orf72 are translated into five dipeptide-repeat proteins (DPRs) in an AUG-independent manner. We previously identified the heterogeneous ribonucleoprotein (hnRNP) A3 as an interactor of the sense repeat RNA that reduces its translation into DPRs. Furthermore, we found that hnRNPA3 is depleted from the nucleus and partially mislocalized to cytoplasmic poly-GA inclusions inC9orf72 patients, suggesting that poly-GA sequesters hnRNPA3 within the cytoplasm. We now...
Source: Acta Neuropathologica - October 22, 2019 Category: Neurology Source Type: research

Production of poly(GA) in C9ORF72 patient motor neurons derived from induced pluripotent stem cells
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - October 16, 2019 Category: Neurology Source Type: research

C9orf72 -specific phenomena associated with frontotemporal dementia and gastrointestinal symptoms in the absence of TDP-43 aggregation
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - October 16, 2019 Category: Neurology Source Type: research

4-Repeat tau seeds and templating subtypes as brain and CSF biomarkers of frontotemporal lobar degeneration
AbstractTo address the need for more meaningful biomarkers of tauopathies, we have developed an ultrasensitive tau seed amplification assay (4R RT-QuIC) for the 4-repeat (4R) tau aggregates of progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and other diseases with 4R tauopathy. The assay detected seeds in 106–109-fold dilutions of 4R tauopathy brain tissue but was orders of magnitude less responsive to brain with other types of tauopathy, such as from Alzheimer ’s disease cases. The analytical sensitivity for synthetic 4R tau fibrils was ~ 50 fM or 2 fg/sample. A n...
Source: Acta Neuropathologica - October 15, 2019 Category: Neurology Source Type: research

A single-center study of the clinicopathologic correlates of gliomas with a MYB or MYBL1 alteration
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - October 7, 2019 Category: Neurology Source Type: research

Isomorphic diffuse glioma is a morphologically and molecularly distinct tumour entity with recurrent gene fusions of MYBL1 or MYB and a benign disease course
AbstractThe “isomorphic subtype of diffuse astrocytoma” was identified histologically in 2004 as a supratentorial, highly differentiated glioma with low cellularity, low proliferation and focal diffuse brain infiltration. Patients typically had seizures since childhood and all were operated on as adults. To define the position of these lesions among brain tumours, we histologically, molecularly and clinically analysed 26 histologically prototypical isomorphic diffuse gliomas. Immunohistochemically, they were GFAP-positive, MAP2-, OLIG2- and CD34-negative, nuclear ATRX-expression was retained and proli feration ...
Source: Acta Neuropathologica - September 27, 2019 Category: Neurology Source Type: research

The basis of clinicopathological heterogeneity in TDP-43 proteinopathy
AbstractTransactive response DNA-binding protein 43  kDa (TDP-43) was identified as a major disease-associated component in the brain of patients with amyotrophic lateral sclerosis (ALS), as well as the largest subset of patients with frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), which characteristically exhibits cytoplas mic inclusions that are positive for ubiquitin but negative for tau and α-synuclein. TDP-43 pathology occurs in distinct brain regions, involves disparate brain networks, and features accumulation of misfolded proteins in various cell types and in different neuroanat...
Source: Acta Neuropathologica - September 25, 2019 Category: Neurology Source Type: research

Correction to: ADAR2 mislocalization and widespread RNA editing aberrations in C9orf72-mediated ALS/FTD
The original article was published erroneously without mentioning the support of the U.S. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - September 25, 2019 Category: Neurology Source Type: research

The active contribution of OPCs to neuroinflammation is mediated by LRP1
AbstractOligodendrocyte progenitor cells (OPCs) account for about 5% of total brain and spinal cord cells, giving rise to myelinating oligodendrocytes that provide electrical insulation to neurons of the CNS. OPCs have also recently been shown to regulate inflammatory responses and glial scar formation, suggesting functions that extend beyond myelination. Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifaceted phagocytic receptor that is highly expressed in several CNS cell types, including OPCs. Here, we have generated an oligodendroglia-specific knockout of LRP1, which presents with normal myelin deve...
Source: Acta Neuropathologica - September 23, 2019 Category: Neurology Source Type: research

On the journey to uncover the causes of selective cellular and regional vulnerability in neurodegeneration
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - September 23, 2019 Category: Neurology Source Type: research

Evidence of corticofugal tau spreading in patients with frontotemporal dementia
AbstractCommon neurodegenerative diseases feature progressive accumulation of disease-specific protein aggregates in selectively vulnerable brain regions. Increasing experimental evidence suggests that misfolded disease proteins exhibit prion-like properties, including the ability to seed corruptive templating and self-propagation along axons. Direct evidence for transneuronal spread in patients, however, remains limited. To test predictions made by the transneuronal spread hypothesis in human tissues, we asked whether tau deposition within axons of the corticospinal and corticopontine pathways can be predicted based on cl...
Source: Acta Neuropathologica - September 20, 2019 Category: Neurology Source Type: research

White matter DNA methylation profiling reveals deregulation of HIP1 , LMAN2 , MOBP , and other loci in multiple system atrophy
AbstractMultiple system atrophy (MSA) is a fatal late-onset neurodegenerative disease. Although presenting with distinct pathological hallmarks, which in MSA consist of glial cytoplasmic inclusions (GCIs) containing fibrillar α-synuclein in oligodendrocytes, both MSA and Parkinson’s disease are α-synucleinopathies. Pathologically, MSA can be categorized into striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA) or mixed subtypes. Despite extensive research, the regional vulnerability of the brain to M SA pathology remains poorly understood. Genetic, epigenetic and environmental factors hav...
Source: Acta Neuropathologica - September 17, 2019 Category: Neurology Source Type: research

Recurrent non-canonical histone H3 mutations in spinal cord diffuse gliomas
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - September 11, 2019 Category: Neurology Source Type: research

Subcortical TDP-43 pathology patterns validate cortical FTLD-TDP subtypes and demonstrate unique aspects of C9orf72 mutation cases
AbstractFrontotemporal lobar degeneration with TDP-43 immunoreactive (TDP-ir) inclusions (FTLD-TDP) is sub-classified based on the pattern of neocortical pathology, with each subtype showing clinical and genetic correlations. Recent studies indicate that accurate subtyping of cases may be important to help identify genetic risk factors and develop biomarkers. Although most FTLD-TDP cases are easily classified, some do not match well to one of the existing subtypes. In particular, cases with theC9orf72 repeat expansion (C9+) have been reported to show FTLD-TDP type A, type B or a combination of A and B pathology (A  ...
Source: Acta Neuropathologica - September 8, 2019 Category: Neurology Source Type: research

Lewy-related pathology exhibits two anatomically and genetically distinct progression patterns: a population-based study of Finns aged 85+
AbstractAccording to a generally accepted concept Lewy-related pathology (LRP) follows hierarchical caudo-rostral progression. LRP is also frequently present concomitantly with Alzheimer ’s disease (AD), and it has been hypothesized that AD-associated LRP forms a distinct type of α-synucleinopathy, where LRP originates in the amygdala. The frequency of distinct forms of LRP progression types has not been studied in a population-based setting. We investigated the distribution and progression of LRP and its relation to AD pathology andapolipoprotein (APOE)ε4 in a population-based sample of Finns aged over...
Source: Acta Neuropathologica - September 6, 2019 Category: Neurology Source Type: research

Correction to: Endogenous oligodendroglial alpha-synuclein and TPPP/p25 α orchestrate alpha-synuclein pathology in experimental multiple system atrophy models
he original version of this article (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - September 2, 2019 Category: Neurology Source Type: research

Correction to: Ketogenic diet ameliorates axonal defects and promotes myelination in Pelizaeus –Merzbacher disease
The original article was published (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - September 2, 2019 Category: Neurology Source Type: research

FOCAD loss impacts microtubule assembly, G2/M progression and patient survival in astrocytic gliomas
AbstractIn search of novel genes associated with glioma pathogenesis, we have previously shown frequent deletions of theKIAA1797/FOCAD gene in malignant gliomas, and a tumor suppressor function of the encoded focadhesin impacting proliferation and migration of glioma cells in vitro and in vivo. Here, we examined an association of reducedFOCAD gene copy number with overall survival of patients with astrocytic gliomas, and addressed the molecular mechanisms that govern the suppressive effect of focadhesin on glioma growth.FOCAD loss was associated with inferior outcome in patients with isocitrate dehydrogenase 1 or 2 (IDH)-m...
Source: Acta Neuropathologica - August 30, 2019 Category: Neurology Source Type: research

An update on the central nervous system manifestations of Li –Fraumeni syndrome
AbstractLi –Fraumeni syndrome (LFS), caused by the germline mutations in theTP53 gene, leads to significant lifetime risk to cancer in the central nervous system. Recognition of LFS, and elucidating its underlying cause has had a remarkable effect on our knowledge of the biology of brain tumors and represents a significant opportunity for cancer surveillance and screening. In this review, we discuss the historical context of the LFS with an emphasis on the clinicopathologic implications in clincal diagnosis, germline testing, and clinical management of brain tumor patients. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - August 29, 2019 Category: Neurology Source Type: research

MSTO1 mutations cause mtDNA depletion, manifesting as muscular dystrophy with cerebellar involvement
We present extensive phenotypic and genetic data from 12 independent families, including 15 new patients harbouring a broad array of bi-allelicMSTO1 pathogenic variants, and we provide functional characterization from sevenMSTO1-related disease patient fibroblasts. Bi-allelic loss-of-function variants inMSTO1 manifest clinically with a remarkably consistent phenotype of childhood-onset muscular dystrophy, corticospinal tract dysfunction and early-onset non-progressive cerebellar atrophy. MSTO1 protein was not detectable in the cultured fibroblasts of all seven patients evaluated, suggesting that pathogenic variants result ...
Source: Acta Neuropathologica - August 28, 2019 Category: Neurology Source Type: research

The dystroglycan receptor maintains glioma stem cells in the vascular niche
AbstractGlioblastomas (GBMs) are malignant central nervous system (CNS) neoplasms with a very poor prognosis. They display cellular hierarchies containing self-renewing tumourigenic glioma stem cells (GSCs) in a complex heterogeneous microenvironment. One proposed GSC niche is the extracellular matrix (ECM)-rich perivascular bed of the tumour. Here, we report that the ECM binding dystroglycan (DG) receptor is expressed and functionally glycosylated on GSCs residing in the perivascular niche. Glycosylated αDG is highly expressed and functional on the most aggressive mesenchymal-like (MES-like) GBM tumour compartment. ...
Source: Acta Neuropathologica - August 27, 2019 Category: Neurology Source Type: research

The TMEM106B FTLD-protective variant, rs1990621, is also associated with increased neuronal proportion
AbstractApart from amyloid β deposition and tau neurofibrillary tangles, Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuronal loss and astrocytosis in the cerebral cortex. The goal of this study is to investigate genetic factors associated with the neuronal proportion in health and disease. To i dentify cell-autonomous genetic variants associated with neuronal proportion in cortical tissues, we inferred cellular population structure from bulk RNA-Seq derived from 1536 individuals. We identified the variant rs1990621 located in theTMEM106B gene region as significantly associated with neuro...
Source: Acta Neuropathologica - August 26, 2019 Category: Neurology Source Type: research

Granulovacuolar degeneration bodies are neuron-selective lysosomal structures induced by intracellular tau pathology
AbstractGranulovacuolar degeneration bodies (GVBs) are membrane-bound vacuolar structures harboring a dense core that accumulate in the brains of patients with neurodegenerative disorders, including Alzheimer ’s disease and other tauopathies. Insight into the origin of GVBs and their connection to tau pathology has been limited by the lack of suitable experimental models for GVB formation. Here, we used confocal, automated, super-resolution and electron microscopy to demonstrate that the seeding of tau pathology triggers the formation of GVBs in different mouse models in vivo and in primary mouse neurons in vitro. Se...
Source: Acta Neuropathologica - August 26, 2019 Category: Neurology Source Type: research

Early defects in translation elongation factor 1 α levels at excitatory synapses in α-synucleinopathy
AbstractCognitive decline and dementia in neurodegenerative diseases are associated with synapse dysfunction and loss, which may precede neuron loss by several years. While misfolded and aggregated α-synuclein is recognized in the disease progression of synucleinopathies, the nature of glutamatergic synapse dysfunction and loss remains incompletely understood. Using fluorescence-activated synaptosome sorting (FASS), we enriched excitatory glutamatergic synaptosomes from mice overexpressing hu man alpha-synuclein (h-αS) and wild-type littermates to unprecedented purity. Subsequent label-free proteomic quantifica...
Source: Acta Neuropathologica - August 25, 2019 Category: Neurology Source Type: research

Dissecting the genetic basis of focal cortical dysplasia: a large cohort study
In conclusion, this study indicates that mMCD/FCD1 and FCD2/HME are two distinct genetic entities: while all FCD2/HME are mosaic mTORopathies, mMCD/FCD1 are not caused by mTOR-pathway-hyperactivating variants, and  ~ 30% of the cases are related to glycosylation defects. We provide a framework for efficient genetic testing in FCD/HME, linking neuropathology to genetic findings and emphasizing the usefulness of molecular evaluation in the pediatric epileptic neurosurgical population. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - August 22, 2019 Category: Neurology Source Type: research

Controversies about the subcellular localization and mechanisms of action of the Alzheimer's disease-protective CD33 splice variant
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - August 21, 2019 Category: Neurology Source Type: research

Correction to: An update on the CNS manifestations of neurofibromatosis type 2
The article An update on the CNS manifestations of neurofibromatosis type 2, written by Shannon Coy, Rumana Rashid, Anat Stemmer ‑Rachamimov and Sandro Santagata, was originally published electronically on the publisher’s internet portal (currently SpringerLink) on 04 June 2019 without open access. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - August 19, 2019 Category: Neurology Source Type: research

Epigenetic loss of RNA-methyltransferase NSUN5 in glioma targets ribosomes to drive a stress adaptive translational program
AbstractTumors have aberrant proteomes that often do not match their corresponding transcriptome profiles. One possible cause of this discrepancy is the existence of aberrant RNA modification landscapes in the so-called epitranscriptome. Here, we report that human glioma cells undergo DNA methylation-associated epigenetic silencing of NSUN5, a candidate RNA methyltransferase for 5-methylcytosine. In this setting, NSUN5 exhibits tumor-suppressor characteristics in vivo glioma models. We also found that NSUN5 loss generates an unmethylated status at the C3782 position of 28S rRNA that drives an overall depletion of protein s...
Source: Acta Neuropathologica - August 18, 2019 Category: Neurology Source Type: research

MYCN amplification drives an aggressive form of spinal ependymoma
AbstractSpinal ependymal tumors form a histologically and molecularly heterogeneous group of tumors with generally good prognosis. However, their treatment can be challenging if infiltration of the spinal cord or dissemination throughout the central nervous system (CNS) occurs and, in these cases, clinical outcome remains poor. Here, we describe a new and relatively rare subgroup of spinal ependymal tumors identified using DNA methylation profiling that is distinct from other molecular subgroups of ependymoma. Copy number variation plots derived from DNA methylation arrays showedMYCN amplification as a characteristic genet...
Source: Acta Neuropathologica - August 13, 2019 Category: Neurology Source Type: research

A β-induced acceleration of Alzheimer-related τ-pathology spreading and its association with prion protein
AbstractExtracellular deposition of amyloid β-protein (Aβ) in amyloid plaques and intracellular accumulation of abnormally phosphorylated τ-protein (p-τ) in neurofibrillary tangles (NFTs) represent pathological hallmark lesions of Alzheimer’s disease (AD). Both lesions develop in parallel in the human brain throughout the preclinical an d clinical course of AD. Nevertheless, it is not yet clear whether there is a direct link between Aβ and τ pathology or whether other proteins are involved in this process. To address this question, we crossed amyloid precursor protein (APP) transgenic mice ...
Source: Acta Neuropathologica - August 13, 2019 Category: Neurology Source Type: research

Calling α-synuclein a prion is scientifically justifiable
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - August 11, 2019 Category: Neurology Source Type: research

Alpha-synuclein: prion or prion-like?
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - August 11, 2019 Category: Neurology Source Type: research

The basis of cellular and regional vulnerability in Alzheimer ’s disease
AbstractAlzheimer ’s disease (AD) differentially and specifically affects brain regions and neuronal cell types in a predictable pattern. Damage to the brain appears to spread and worsens with time, taking over more regions and activating multiple stressors that can converge to promote vulnerability of certain cell types. At the same time, other cell types and brain regions remain intact in the face of this onslaught of neuropathology. Although neuropathologic descriptions of AD have been extensively expanded and mapped over the last several decades, our understanding of the mechanisms underlying how certain regions ...
Source: Acta Neuropathologica - August 6, 2019 Category: Neurology Source Type: research

Precise detection of low-level somatic mutation in resected epilepsy brain tissue
AbstractLow-level somatic mutations have been shown to be the major genetic etiology of intractable epilepsy. The extents thereof, however, have yet to be systematically and accurately explored in a large cohort of resected epilepsy brain tissues. Moreover, clinically useful and precise analysis tools for detecting low-level somatic mutations from unmatched formalin-fixed paraffin-embedded (FFPE) brain samples, the most clinically relevant samples, are still lacking. In total, 446 tissues samples from 232 intractable epilepsy patients with various brain pathologies were analyzed using deep sequencing (average read depth, 1...
Source: Acta Neuropathologica - August 2, 2019 Category: Neurology Source Type: research

Dipeptide repeat (DPR) pathology in the skeletal muscle of ALS patients with C9ORF72 repeat expansion
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - August 1, 2019 Category: Neurology Source Type: research

Neurotoxicology: an update on epidemiology, mechanisms, and pathology
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - July 31, 2019 Category: Neurology Source Type: research

Detrimental and protective action of microglial extracellular vesicles on myelin lesions: astrocyte involvement in remyelination failure
AbstractMicroglia are highly plastic immune cells which exist in a continuum of activation states. By shaping the function of oligodendrocyte precursor cells (OPCs), the brain cells which differentiate to myelin-forming cells, microglia participate in both myelin injury and remyelination during multiple sclerosis. However, the mode(s) of action of microglia in supporting or inhibiting myelin repair is still largely unclear. Here, we analysed the effects of extracellular vesicles (EVs) produced in vitro by either pro-inflammatory or pro-regenerative microglia on OPCs at demyelinated lesions caused by lysolecithin injection ...
Source: Acta Neuropathologica - July 29, 2019 Category: Neurology Source Type: research

Impact of TREM2 risk variants on brain region-specific immune activation and plaque microenvironment in Alzheimer ’s disease patient brain samples
AbstractIdentification of multiple immune-related genetic risk factors for sporadic AD (sAD) have put the immune system center stage in mechanisms underlying this disorder. Comprehensive analysis of microglia in different stages of AD in human brains revealed microglia activation to follow the progression of AD neuropathological changes and requiring the co-occurrence of beta-Amyloid (A β) and tau pathology. Carriers of AD-associated risk variants in TREM2 (Triggering receptor expressed on myeloid cells 2) showed a reduction of plaque-associated microglia and a substantial increase in dystrophic neurites and overall p...
Source: Acta Neuropathologica - July 25, 2019 Category: Neurology Source Type: research

The neuropathology of fatal encephalomyelitis in human Borna virus infection
This study aims at raising awareness to human bornavirus encephalitis as differential diagnosis in lymphocytic scleros ing panencephalomyelitis. A higher attention to human BoDV-1 infection by health professionals may likely increase the detection of more cases and foster a clearer picture of the disease. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - July 25, 2019 Category: Neurology Source Type: research

Splicing repression is a major function of TDP-43 in motor neurons
AbstractNuclear depletion of TDP-43, an essential RNA binding protein, may underlie neurodegeneration in amyotrophic lateral sclerosis (ALS). As several functions have been ascribed to this protein, the critical role(s) of TDP-43 in motor neurons that may be compromised in ALS remains unknown. We show here that TDP-43 mediated splicing repression, which serves to protect the transcriptome by preventing aberrant splicing, is central to the physiology of motor neurons. Expression inDrosophila TDP-43 knockout models of a chimeric repressor, comprised of the RNA recognition domain of TDP-43 fused to an unrelated splicing repre...
Source: Acta Neuropathologica - July 21, 2019 Category: Neurology Source Type: research

C9orf72 intermediate repeats are associated with corticobasal degeneration, increased C9orf72 expression and disruption of autophagy
AbstractMicrosatellite repeat expansion disease loci can exhibit pleiotropic clinical and biological effects depending on repeat length. Large expansions inC9orf72 (100s –1000s of units) are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). However, whether intermediate expansions also contribute to neurodegenerative disease is not well understood. Several studies have identified intermediate repeats in Par kinson’s disease patients, but the association was not found in autopsy-confirmed cases. We hypothesized that intermediateC9orf72 repeats are a genet...
Source: Acta Neuropathologica - July 19, 2019 Category: Neurology Source Type: research

Contextualizing the pathology in the essential tremor cerebellar cortex: a patholog-omics approach
AbstractSeveral morphological changes, centered in/around Purkinje cells (PCs), have been identified in the cerebellum of essential tremor (ET) patients. These changes have not been contextualized within a broader degenerative disease spectrum, limiting their interpretability. To address this, we compared the severity and patterning of degenerative changes within the cerebellar cortex in patients with ET, other neurodegenerative disorders of the cerebellum (spinocerebellar ataxias (SCAs), multiple system atrophy (MSA)], and other disorders that may involve the cerebellum [Parkinson ’s disease (PD), dystonia]. Using a...
Source: Acta Neuropathologica - July 16, 2019 Category: Neurology Source Type: research

Novel Alzheimer ’s disease risk genes: exhaustive investigation is paramount
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - July 11, 2019 Category: Neurology Source Type: research

Routine RNA sequencing of formalin-fixed paraffin-embedded specimens in neuropathology diagnostics identifies diagnostically and therapeutically relevant gene fusions
AbstractMolecular markers have become pivotal in brain tumor diagnostics. Mutational analyses by targeted next-generation sequencing of DNA and array-based DNA methylation assessment with copy number analyses are increasingly being used in routine diagnostics. However, the broad variety of gene fusions occurring in brain tumors is marginally covered by these technologies and often only assessed by targeted assays. Here, we assessed the feasibility and clinical value of investigating gene fusions in formalin-fixed paraffin-embedded (FFPE) tumor tissues by next-generation mRNA sequencing in a routine diagnostic setting. Afte...
Source: Acta Neuropathologica - July 4, 2019 Category: Neurology Source Type: research

Alzheimer ’s disease clinical variants show distinct regional patterns of neurofibrillary tangle accumulation
In this study, we explored the regional distribution of NFT pathology and its relationship to AD presentation across five different clinical syndromes. We assessed NFT density throughout six selected neocortical and hippocampal regions using thioflavin-S fluorescent microscopy in a well-characterized clinicopathological cohort of pure AD cases enrich ed for atypical clinical presentations. Subjects underwent apolipoprotein E genotyping and neuropsychological testing. Main cognitive domains (executive, visuospatial, language, and memory function) were assessed using an established compositez score. Our results showed that N...
Source: Acta Neuropathologica - June 26, 2019 Category: Neurology Source Type: research

Rosette-forming glioneuronal tumors share a distinct DNA methylation profile and mutations in FGFR1 , with recurrent co-mutation of PIK3CA and NF1
AbstractRosette-forming glioneuronal tumor (RGNT) is a rare brain neoplasm that primarily affects young adults. Although alterations affecting the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling pathway have been associated with this low-grade entity, comprehensive molecular investigations of RGNT in larger series have not been performed to date, and an integrated view of their genetic and epigenetic profiles is still lacking. Here we describe a genome-wide DNA methylation and targeted sequencing-based characterization of a molecularly distinct class of tumors (n = 30), ...
Source: Acta Neuropathologica - June 26, 2019 Category: Neurology Source Type: research

Evidence for bidirectional and trans -synaptic parasympathetic and sympathetic propagation of alpha-synuclein in rats
In this study, we tested this hypothesis by directly injecting preformed asyn fibrils into the duodenum wall of wild-type rats and transgenic rats with excess levels of human asyn. We provide a meticulous characterization of the bacterial artificial chromosome (BAC) transgenic rat mo del with respect to initial propagation of pathological asyn along the parasympathetic and sympathetic pathways to the brainstem, by performing immunohistochemistry at early time points post-injection. Induced pathology was observed in all key structures along the sympathetic and parasympathetic pat hways (ENS, autonomic ganglia, intermediolat...
Source: Acta Neuropathologica - June 25, 2019 Category: Neurology Source Type: research

Oral and intravenous transmission of α-synuclein fibrils to mice
AbstractParkinson ’s disease and related disorders are neuropathologically characterized by cellular deposits of misfolded and aggregated α-synuclein in the CNS. Disease-associated α-synuclein adopts a conformation that causes it to form oligomers and fibrils, which have reduced solubility, become hyperphosphoryl ated, and contribute to the spatiotemporal spreading of pathology in the CNS. The infectious properties of disease-associated α-synuclein, e.g., by which peripheral route and with which efficiency it can be transmitted, are not fully understood. Here, we investigated the potential of &alpha...
Source: Acta Neuropathologica - June 21, 2019 Category: Neurology Source Type: research

Impairments in contractility and cytoskeletal organisation cause nuclear defects in nemaline myopathy
AbstractNemaline myopathy (NM) is a skeletal muscle disorder caused by mutations in genes that are generally involved in muscle contraction, in particular those related to the structure and/or regulation of the thin filament. Many pathogenic aspects of this disease remain largely unclear. Here, we report novel pathological defects in skeletal muscle fibres of mouse models and patients with NM: irregular spacing and morphology of nuclei; disrupted nuclear envelope; altered chromatin arrangement; and disorganisation of the cortical cytoskeleton. Impairments in contractility are the primary cause of these nuclear defects. We ...
Source: Acta Neuropathologica - June 18, 2019 Category: Neurology Source Type: research