DICER1 syndrome in a young adult with pituitary blastoma
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - October 22, 2021 Category: Neurology Source Type: research

Genetic and epigenetic characterization of posterior pituitary tumors
AbstractPituicytoma (PITUI), granular cell tumor (GCT), and spindle cell oncocytoma (SCO) are rare tumors of the posterior pituitary. Histologically, they may be challenging to distinguish and have been proposed to represent a histological spectrum of a single entity. We performed targeted next-generation sequencing, DNA methylation profiling, and copy number analysis on 47 tumors (14 PITUI; 12 GCT; 21 SCO) to investigate molecular features and explore possibilities of clinically meaningful tumor subclassification. We detected two main epigenomic subgroups by unsupervised clustering of DNA methylation data, though the over...
Source: Acta Neuropathologica - October 18, 2021 Category: Neurology Source Type: research

Tau seeding in chronic traumatic encephalopathy parallels disease severity
AbstractChronic traumatic encephalopathy (CTE), a neurodegenerative tauopathy, is associated with behavioral, mood and cognitive impairment, including dementia. Tauopathies are neurodegenerative diseases whose neuropathological phenotypes are characterized by distinct histopathologic features of tau pathology, which progressively deposit throughout the brain. In certain tauopathies, especially Alzheimer ’s disease (AD), tau deposition appears to follow brain network connections. Experimental evidence suggests that the progression of tau pathology in humans, mouse and cell models could be explained by tau seeds that a...
Source: Acta Neuropathologica - October 9, 2021 Category: Neurology Source Type: research

Analyzing microglial phenotypes across neuropathologies: a practical guide
AbstractAs extremely sensitive immune cells, microglia act as versatile watchdogs of the central nervous system (CNS) that tightly control tissue homeostasis. Therefore, microglial activation is an early and easily detectable hallmark of virtually all neuropsychiatric, neuro-oncological, neurodevelopmental, neurodegenerative and neuroinflammatory diseases. The recent introduction of novel high-throughput technologies and several single-cell methodologies as well as advances in epigenetic analyses helped to identify new microglia expression profiles, enhancer-landscapes and local signaling cues that defined diverse previous...
Source: Acta Neuropathologica - October 8, 2021 Category: Neurology Source Type: research

Nuclear depletion of RNA-binding protein ELAVL3 (HuC) in sporadic and familial amyotrophic lateral sclerosis
AbstractAmyotrophic lateral sclerosis is a progressive fatal neurodegenerative disease caused by loss of motor neurons and characterized neuropathologically in almost all cases by nuclear depletion and cytoplasmic aggregation of TDP-43, a nuclear RNA-binding protein (RBP). We identified ELAVL3 as one of the most downregulated genes in our transcriptome profiles of laser captured microdissection of motor neurons from sporadic ALS nervous systems and the most dysregulated of all RBPs. Neuropathological characterizations showed ELAVL3 nuclear depletion in a great percentage of remnant motor neurons, sometimes accompanied by c...
Source: Acta Neuropathologica - October 7, 2021 Category: Neurology Source Type: research

Frontal white matter lesions in Alzheimer ’s disease are associated with both small vessel disease and AD-associated cortical pathology
AbstractCerebral white matter lesions (WML) encompass axonal loss and demyelination and are assumed to be associated with small vessel disease (SVD)-related ischaemia. However, our previous study in the parietal lobe white matter revealed that WML in Alzheimer ’s disease (AD) are linked with degenerative axonal loss secondary to the deposition of cortical AD pathology. Furthermore, neuroimaging data suggest that pathomechanisms for the development of WML differ between anterior and posterior lobes with AD-associated degenerative mechanism driving poster ior white matter disruption, and both AD-associated degenerative...
Source: Acta Neuropathologica - October 4, 2021 Category: Neurology Source Type: research

TMEM106B modifies TDP-43 pathology in human ALS brain and cell-based models of TDP-43 proteinopathy
AbstractThe neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TAR DNA-binding protein-43 (TDP-43) inclusions (FTLD-TDP) share the neuropathological hallmark of aggregates of TDP-43. However, factors governing the severity and regional distribution of TDP-43 pathology, which may account for the divergent clinical presentations of ALS and FTLD-TDP, are not well understood. Here, we investigated the influence of genotypes atTMEM106B, a locus associated with risk for FTLD-TDP, and hexanucleotide repeat expansions inC9orf72, a known genetic cause for both ALS and FTLD-TDP,...
Source: Acta Neuropathologica - September 19, 2021 Category: Neurology Source Type: research

Phenotypic diversity of genetic Creutzfeldt –Jakob disease: a histo-molecular-based classification
AbstractThe current classification of sporadic Creutzfeldt –Jakob disease (sCJD) includes six major clinicopathological subtypes defined by the physicochemical properties of the protease-resistant core of the pathologic prion protein (PrPSc), defining two major PrPSc types  (i.e., 1 and 2), and the methionine (M)/valine (V) polymorphic codon 129 of the prion protein gene (PRNP). How these sCJD subtypes relate to the well-documented phenotypic heterogeneity of genetic CJD (gCJD) is not fully understood. We analyzed molecular and phenotypic features in 208 individuals affected by gCJD, carrying 17 different mutati...
Source: Acta Neuropathologica - September 19, 2021 Category: Neurology Source Type: research

Seizure-mediated iron accumulation and dysregulated iron metabolism after status epilepticus and in temporal lobe epilepsy
AbstractNeuronal dysfunction due to iron accumulation in conjunction with reactive oxygen species (ROS) could represent an important, yet underappreciated, component of the epileptogenic process. However, to date, alterations in iron metabolism in the epileptogenic brain have not been addressed in detail. Iron-related neuropathology and antioxidant metabolic processes were investigated in resected brain tissue from patients with temporal lobe epilepsy and hippocampal sclerosis (TLE-HS), post-mortem brain tissue from patients who died after status epilepticus (SE) as well as brain tissue from the electrically induced SE rat...
Source: Acta Neuropathologica - September 19, 2021 Category: Neurology Source Type: research

Neuronal spreading and plaque induction of intracellular A β and its disruption of Aβ homeostasis
AbstractThe amyloid-beta peptide (A β) is thought to have prion-like properties promoting its spread throughout the brain in Alzheimer’s disease (AD). However, the cellular mechanism(s) of this spread remains unclear. Here, we show an important role of intracellular Aβ in its prion-like spread. We demonstrate that an intracellular source of Aβ can induce amyloid plaques in vivo via hippocampal injection. We show that hippocampal injection of mouse AD brain homogenate not only induces plaques, but also damages interneurons and affects intracellular Aβ levels in synaptically connected brain areas, p...
Source: Acta Neuropathologica - September 19, 2021 Category: Neurology Source Type: research

Complement-associated loss of CA2 inhibitory synapses in the demyelinated hippocampus impairs memory
AbstractThe complement system is implicated in synapse loss in the MS hippocampus, but the functional consequences of synapse loss remain poorly understood. Here, in post-mortem MS hippocampi with demyelination we find that deposits of the complement component C1q are enriched in the CA2 subfield, are linked to loss of inhibitory synapses and are significantly higher in MS patients with cognitive impairments compared to those with preserved cognitive functions. Using the cuprizone mouse model of demyelination, we corroborated that C1q deposits are highest within the demyelinated dorsal hippocampal CA2 pyramidal layer and c...
Source: Acta Neuropathologica - September 19, 2021 Category: Neurology Source Type: research

HnRNP K mislocalisation is a novel protein pathology of frontotemporal lobar degeneration and ageing and leads to cryptic splicing
AbstractHeterogeneous nuclear ribonucleoproteins (HnRNPs) are a group of ubiquitously expressed RNA-binding proteins implicated in the regulation of all aspects of nucleic acid metabolism. HnRNP K is a member of this highly versatile hnRNP family. Pathological redistribution of hnRNP K to the cytoplasm has been linked to the pathogenesis of several malignancies but, until now, has been underexplored in the context of neurodegenerative disease. Here we show hnRNP K mislocalisation in pyramidal neurons of the frontal cortex to be a novel neuropathological feature that is associated with both frontotemporal lobar degeneration...
Source: Acta Neuropathologica - September 19, 2021 Category: Neurology Source Type: research

Comparing amyloid- β plaque burden with antemortem PiB PET in autosomal dominant and late-onset Alzheimer disease
AbstractPittsburgh compound B (PiB) radiotracer for positron emission tomography (PET) imaging can bind to different types of amyloid- β plaques and blood vessels (cerebral amyloid angiopathy). However, the relative contributions of different plaque subtypes (diffuse versus cored/compact) to in vivo PiB PET signal on a region-by-region basis are incompletely understood. Of particular interest is whether the same staging schemes fo r summarizing amyloid-β burden are appropriate for both late-onset and autosomal dominant forms of Alzheimer disease (LOAD and ADAD). Here, we compared antemortem PiB PET with follow-up...
Source: Acta Neuropathologica - September 19, 2021 Category: Neurology Source Type: research

PSD-93 up-regulates the synaptic activity of corticotropin-releasing hormone neurons in the paraventricular nucleus in depression
This study constitutes the first observation of an increased density of PSD-93-CRH co-localized neurons in the hypothalamic paraventricular nucleus (PVN) of patients with major depression. PSD-93 overexpression in CRH neurons in the PVN induced depressi on-like behaviors in mice, accompanied by increased serum corticosterone level. PSD-93 knockdown relieved the depression-like phenotypes in a lipopolysaccharide (LPS)-induced depression model. Electrophysiological data showed that PSD-93 overexpression increased CRH neurons synaptic activity, while PSD-93 knockdown decreased CRH neurons synaptic activity. Furthermore, ...
Source: Acta Neuropathologica - September 18, 2021 Category: Neurology Source Type: research

GOPC:ROS1 and other ROS1 fusions represent a rare but recurrent drug target in a variety of glioma types
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - September 18, 2021 Category: Neurology Source Type: research

Altered ceramide metabolism is a feature in the extracellular vesicle-mediated spread of alpha-synuclein in Lewy body disorders
AbstractMutations in glucocerebrosidase (GBA) are the most prevalent genetic risk factor for Lewy body disorders (LBD) —collectively Parkinson’s disease, Parkinson’s disease dementia and dementia with Lewy bodies. Despite this genetic association, it remains unclear howGBA mutations increase susceptibility to develop LBD. We investigated relationships between LBD-specific glucocerebrosidase deficits, GBA-related pathways, and α-synuclein levels in brain tissue from LBD and controls, with and withoutGBA mutations. We show that LBD is characterised by altered sphingolipid metabolism with prominent ele...
Source: Acta Neuropathologica - September 13, 2021 Category: Neurology Source Type: research

Correction to: Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is independently associated with dementia and strongly associated with arteriolosclerosis in the oldest-old
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - September 13, 2021 Category: Neurology Source Type: research

Altered ceramide metabolism is a feature in the extracellular vesicle-mediated spread of alpha-synuclein in Lewy body disorders
AbstractMutations in glucocerebrosidase (GBA) are the most prevalent genetic risk factor for Lewy body disorders (LBD) —collectively Parkinson’s disease, Parkinson’s disease dementia and dementia with Lewy bodies. Despite this genetic association, it remains unclear howGBA mutations increase susceptibility to develop LBD. We investigated relationships between LBD-specific glucocerebrosidase deficits, GBA-related pathways, and α-synuclein levels in brain tissue from LBD and controls, with and withoutGBA mutations. We show that LBD is characterised by altered sphingolipid metabolism with prominent ele...
Source: Acta Neuropathologica - September 13, 2021 Category: Neurology Source Type: research

Correction to: Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is independently associated with dementia and strongly associated with arteriolosclerosis in the oldest-old
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - September 13, 2021 Category: Neurology Source Type: research

A network of core and subtype-specific gene expression programs in myositis
AbstractMyositis comprises a heterogeneous group of skeletal muscle disorders which converge on chronic muscle inflammation and weakness. Our understanding of myositis pathogenesis is limited, and many myositis patients lack effective therapies. Using muscle biopsy transcriptome profiles from 119 myositis patients (spanning major clinical and serological disease subtypes) and 20 normal controls, we generated a co-expression network of 8101 dynamically regulated transcripts. This network organized the myositis transcriptome into a map of gene expression modules representing interrelated biological processes and disease sign...
Source: Acta Neuropathologica - September 9, 2021 Category: Neurology Source Type: research

Molecular profiling of pediatric meningiomas shows tumor characteristics distinct from adult meningiomas
AbstractIn contrast to adults, meningiomas are uncommon tumors in childhood and adolescence. Whether adult and pediatric meningiomas differ on a molecular level is unclear. Here we report detailed genomic analyses of 37 pediatric meningiomas by sequencing and DNA methylation profiling. Histologically, the series was dominated by meningioma subtypes with aggressive behavior, with 70% of patients suffering from WHO grade II or III meningiomas. The most frequent cytogenetic aberrations were loss of chromosomes 22 (23/37 [62%]), 1 (9/37 [24%]), 18 (7/37 [19%]), and 14 (5/37 [14%]). Tumors withNF2 alterations exhibited overall ...
Source: Acta Neuropathologica - September 8, 2021 Category: Neurology Source Type: research

Complement component 3 from astrocytes mediates retinal ganglion cell loss during neuroinflammation
AbstractMultiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) characterized by varying degrees of secondary neurodegeneration. Retinal ganglion cells (RGC) are lost in MS in association with optic neuritis but the mechanisms of neuronal injury remain unclear. Complement component C3 has been implicated in retinal and cerebral synaptic pathology that may precede neurodegeneration. Herein, we examined post-mortem MS retinas, and then used a mouse model, experimental autoimmune encephalomyelitis (EAE), to examine the role of C3 in the pathogenesis of RGC loss associated with opti...
Source: Acta Neuropathologica - September 6, 2021 Category: Neurology Source Type: research

Alpha-synuclein pathology of olfactory bulbs/peduncles in the Vantaa85+  cohort exhibit two divergent patterns: a population-based study
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - September 1, 2021 Category: Neurology Source Type: research

A recurrent homozygous ACTN2 variant associated with core myopathy
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - September 1, 2021 Category: Neurology Source Type: research

Alpha-synuclein pathology of olfactory bulbs/peduncles in the Vantaa85+  cohort exhibit two divergent patterns: a population-based study
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - September 1, 2021 Category: Neurology Source Type: research

A recurrent homozygous ACTN2 variant associated with core myopathy
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - September 1, 2021 Category: Neurology Source Type: research

Apolipoprotein E regulates lipid metabolism and α-synuclein pathology in human iPSC-derived cerebral organoids
AbstractAPOE4 is a strong genetic risk factor for Alzheimer ’s disease and Dementia with Lewy bodies; however, how its expression impacts pathogenic pathways in a human-relevant system is not clear. Here using human iPSC-derived cerebral organoid models, we find thatAPOE deletion increases α-synuclein (αSyn) accumulation accompanied with synaptic loss, reduction of GBA levels, lipid droplet accumulation and dysregulation of intracellular organelles. These phenotypes are partially rescued by exogenous apoE2 and apoE3, but not apoE4. Lipidomics analysis detects the increased fatty aci d utilization and chol...
Source: Acta Neuropathologica - August 28, 2021 Category: Neurology Source Type: research

Early white matter pathology in the fornix of the limbic system in Huntington disease
AbstractHuntington disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene. The typical motor symptoms have been associated with basal ganglia pathology. However, psychiatric and cognitive symptoms often precede the motor component and may be due to changes in the limbic system. Recent work has indicated pathology in the hypothalamus in HD but other parts of the limbic system have not been extensively studied. Emerging evidence suggests that changes in HD also include white matter pathology. Here we investigated if the main white matter tract of the limbic system, th...
Source: Acta Neuropathologica - August 26, 2021 Category: Neurology Source Type: research

PATZ1 fusions define a novel molecularly distinct neuroepithelial tumor entity with a broad histological spectrum
AbstractLarge-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly distinct entities, cellular origins and genetic drivers than anticipated from histological assessment. DNA methylation profiling has emerged as a useful tool for robust tumor classification, providing new insights into these heterogeneous molecular classes. This is particularly true for rare CNS tumors with a broad morphological spectrum, which are not possible to assign as separate entities based on histological similarity alone. Here, we describe ...
Source: Acta Neuropathologica - August 21, 2021 Category: Neurology Source Type: research

Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is independently associated with dementia and strongly associated with arteriolosclerosis in the oldest-old
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - August 20, 2021 Category: Neurology Source Type: research

Subgroup and subtype-specific outcomes in adult medulloblastoma
AbstractMedulloblastoma, a common pediatric malignant central nervous system tumour, represent a small proportion of brain tumours in adults. Previously it has been shown that in adults, Sonic Hedgehog (SHH)-activated tumours predominate, with Wingless-type (WNT) and Group 4 being less common, but molecular risk stratification remains a challenge. We performed an integrated analysis consisting of genome-wide methylation profiling, copy number profiling, somatic nucleotide variants and correlation of clinical variables across a cohort of 191 adult medulloblastoma cases identified through the Medulloblastoma Advanced Genomic...
Source: Acta Neuropathologica - August 18, 2021 Category: Neurology Source Type: research

Correction to: Single ‑cell profiling of myasthenia gravis identifies a pathogenic T cell signature
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - August 18, 2021 Category: Neurology Source Type: research

Subgroup and subtype-specific outcomes in adult medulloblastoma
AbstractMedulloblastoma, a common pediatric malignant central nervous system tumour, represent a small proportion of brain tumours in adults. Previously it has been shown that in adults, Sonic Hedgehog (SHH)-activated tumours predominate, with Wingless-type (WNT) and Group 4 being less common, but molecular risk stratification remains a challenge. We performed an integrated analysis consisting of genome-wide methylation profiling, copy number profiling, somatic nucleotide variants and correlation of clinical variables across a cohort of 191 adult medulloblastoma cases identified through the Medulloblastoma Advanced Genomic...
Source: Acta Neuropathologica - August 18, 2021 Category: Neurology Source Type: research

Correction to: Single ‑cell profiling of myasthenia gravis identifies a pathogenic T cell signature
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - August 18, 2021 Category: Neurology Source Type: research

A glutaminyl cyclase-catalyzed α-synuclein modification identified in human synucleinopathies
AbstractParkinson ’s disease (PD) is a progressive neurodegenerative disorder that is neuropathologically characterized by degeneration of dopaminergic neurons of the substantia nigra (SN) and formation of Lewy bodies and Lewy neurites composed of aggregated α-synuclein. Proteolysis of α-synuclein by matrix metal loproteinases was shown to facilitate its aggregation and to affect cell viability. One of the proteolysed fragments, Gln79-α-synuclein, possesses a glutamine residue at its N-terminus. We argue that glutaminyl cyclase (QC) may catalyze the pyroglutamate (pGlu)79-α-synuclein formation...
Source: Acta Neuropathologica - August 14, 2021 Category: Neurology Source Type: research

R1441G but not G2019S mutation enhances LRRK2 mediated Rab10 phosphorylation in human peripheral blood neutrophils
AbstractHeterozygous gain-of-kinase function variants inLRRK2 (leucine-rich repeat kinase 2) cause 1 –2% of all cases of Parkinson’s disease (PD) albeit with incomplete and age-dependent penetrance. All pathogenic LRRK2 mutations reside within the two catalytic domains of LRRK2—either in its kinase domain (e.g. G2019S) with modest effect or its ROC-COR GTPase domain (e.g. R1441G/H) with large effect on LRRK2 kinase activity. We have previously reported assays to interrogate LRRK2 kinase pathway activity in human bio-samples measuring phosphorylation of its endogenous substrate Rab10, that mirrors LRRK2 ki...
Source: Acta Neuropathologica - August 14, 2021 Category: Neurology Source Type: research