Intellectual disability: dendritic anomalies and emerging genetic perspectives
AbstractIntellectual disability (ID) corresponds to several neurodevelopmental disorders of heterogeneous origin in which cognitive deficits are commonly associated with abnormalities of dendrites and dendritic spines. These histological changes in the brain serve as a proxy for underlying deficits in neuronal network connectivity, mostly a result of genetic factors. Historically, chromosomal abnormalities have been reported by conventional karyotyping, targeted fluorescence in situ hybridization (FISH), and chromosomal microarray analysis. More recently, cytogenomic mapping, whole-exome sequencing, and bioinformatic minin...
Source: Acta Neuropathologica - November 23, 2020 Category: Neurology Source Type: research

Malignant transformation of a polymorphous low grade neuroepithelial tumor of the young (PLNTY)
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - November 23, 2020 Category: Neurology Source Type: research

Primary mismatch repair deficient IDH-mutant astrocytoma (PMMRDIA) is a distinct type with a poor prognosis
AbstractDiffuse IDH-mutant astrocytoma mostly occurs in adults and carries a favorable prognosis compared to IDH-wildtype malignant gliomas. Acquired mismatch repair deficiency is known to occur in recurrent IDH-mutant gliomas as resistance mechanism towards alkylating chemotherapy. In this multi-institutional study, we report a novel epigenetic group of 32 IDH-mutant gliomas with proven or suspected hereditary mismatch repair deficiency. None of the tumors exhibited a combined 1p/19q deletion. These primary mismatch repair-deficient IDH-mutant astrocytomas (PMMRDIA) were histologically high-grade and were mainly found in ...
Source: Acta Neuropathologica - November 20, 2020 Category: Neurology Source Type: research

Lewy pathology of the esophagus correlates with the progression of Lewy body disease: a Japanese cohort study of autopsy cases
AbstractLewy body disease (LBD) is a spectrum of progressive neurodegenerative disorders characterized by the wide distribution of Lewy bodies and neurites in the central and peripheral nervous system (CNS, PNS). Clinical diagnoses include Parkinson ’s disease (PD), dementia with Lewy bodies, or pure autonomic failure. All types of LBD are accompanied by non-motor symptoms (NMSs) including gastrointestinal dysfunctions such as constipation. Its relationship to Lewy body-related α-synucleinopathy (Lewy pathology) of the enteric nervous system (ENS) is attracting attention because it can precede the motor symptom...
Source: Acta Neuropathologica - November 5, 2020 Category: Neurology Source Type: research

Correction to: Antibody against TDP-43 phosphorylated at serine 369 suggests conformational differences of TDP-43 aggregates among FTLD-TDP subtypes
Due to a mistake with incorrect assignment of the originally planned amino acid residues 368-379 to the protein sequence of TDP-43 for antibody production by the contracted company, a peptide corresponding to amino acids 362-373 with a phosphorylated serin at 369 instead of a peptide corresponding to amino acids 368-379 with a phosphorylated serin at 375 was synthesized and used for antibody generation and purification. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - November 3, 2020 Category: Neurology Source Type: research

Correction to: Epigenomic, genomic, and transcriptomic landscape of schwannomatosis
In the original publication, corresponding author information missed indicating that Dr. Zadeh. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - October 28, 2020 Category: Neurology Source Type: research

Brain arteriolosclerosis
AbstractBrain arteriolosclerosis (B-ASC), characterized by pathologic arteriolar wall thickening, is a common finding at autopsy in aged persons and is associated with cognitive impairment. Hypertension and diabetes are widely recognized as risk factors for B-ASC. Recent research indicates other and more complex risk factors and pathogenetic mechanisms. Here, we describe aspects of the unique architecture of brain arterioles, histomorphologic features of B-ASC, relevant neuroimaging findings, epidemiology and association with aging, established genetic risk factors, and the co-occurrence of B-ASC with other neuropathologic...
Source: Acta Neuropathologica - October 24, 2020 Category: Neurology Source Type: research

Infratentorial C11orf95 -fused gliomas share histologic, immunophenotypic, and molecular characteristics of supratentorial RELA -fused ependymoma
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - October 24, 2020 Category: Neurology Source Type: research

Correction to: C11orf95-RELA reprograms 3D epigenome in supratentorial ependymoma
In the original publication, Fig.  1 was incorrectly published with same two histograms at the bottom. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - October 23, 2020 Category: Neurology Source Type: research

Accumulation of  amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer’s disease models and human brains
AbstractSeveral lines of recent evidence indicate that the amyloid precursor protein-derived C-terminal fragments (APP-CTFs) could correspond to an etiological trigger of Alzheimer ’s disease (AD) pathology. Altered mitochondrial homeostasis is considered an early event in AD development. However, the specific contribution of APP-CTFs to mitochondrial structure, function, and mitophagy defects remains to be established. Here, we demonstrate in neuroblastoma SH-SY5Y cells exp ressing either APP Swedish mutations, or the β-secretase-derived APP-CTF fragment (C99) combined with β- and γ-secretase inhibit...
Source: Acta Neuropathologica - October 20, 2020 Category: Neurology Source Type: research

MOG-expressing teratoma followed by MOG-IgG-positive optic neuritis
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - October 19, 2020 Category: Neurology Source Type: research

MOG expressing teratoma followed by MOG-IgG-positive optic neuritis
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - October 19, 2020 Category: Neurology Source Type: research

Neuropathological evaluation of a vertebrate brain aged  ~ 245 years
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - October 16, 2020 Category: Neurology Source Type: research

Epigenomic, genomic, and transcriptomic landscape of schwannomatosis
AbstractSchwannomatosis (SWNTS) is a genetic cancer predisposition syndrome that manifests as multiple and often painful neuronal tumors called schwannomas (SWNs). While germline mutations inSMARCB1 orLZTR1, plus somatic mutations inNF2 and loss of heterozygosity in chromosome 22q have been identified in a subset of patients, little is known about the epigenomic and genomic alterations that drive SWNTS-related SWNs (SWNTS-SWNs) in a majority of the cases. We performed multiplatform genomic analysis and established the molecular signature of SWNTS-SWNs. We show that SWNTS-SWNs harbor distinct genomic features relative to th...
Source: Acta Neuropathologica - October 5, 2020 Category: Neurology Source Type: research

Familial adenomatous polyposis associated craniopharyngioma secondary to both germline and somatic mutations in the APC gene
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - October 5, 2020 Category: Neurology Source Type: research

Direct neural transmission of vCJD/BSE in macaque after finger incision
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - October 5, 2020 Category: Neurology Source Type: research

Neuronal activity modulates alpha-synuclein aggregation and spreading in organotypic brain slice cultures and in vivo
AbstractAlpha-synuclein ( αSyn) preformed fibrils (PFF) induce endogenous αSyn aggregation leading to reduced synaptic transmission. Neuronal activity modulates release of αSyn; however, whether neuronal activity regulates the spreading of αSyn pathology remains elusive. Here, we established a hippocampal slice culture s ystem from wild-type (WT) mice and found that both Ca2+ influx and the uptake of αSyn PFF were higher in the CA3 than in the CA1 sub-region. Pharmacologically enhancing neuronal activity substantially increased αSyn pathology in αSyn PFF-treated hippocampal or midb...
Source: Acta Neuropathologica - October 5, 2020 Category: Neurology Source Type: research

Impairment of the mitochondrial one-carbon metabolism enzyme SHMT2 causes a novel brain and heart developmental syndrome
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - October 4, 2020 Category: Neurology Source Type: research

Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology
We report the establishment a large cohort of unique organoids and patient-derived orthotopic xenografts (PDOX) of various glioma subtypes, including gliomas with mutations inIDH1, and paired longitudinal PDOX from primary and recurrent tumors of the same patient. We show that glioma PDOXs enable long-term propagation of patient tumors and represent clinically relevant patient avatars that retain histopathological, genetic, epigenetic, and transcriptomic features of parental tumors. We find no evidence of mouse-specific clonal evolution in glioma PDOXs. Our cohort captures individual molecular genotypes for precision medic...
Source: Acta Neuropathologica - October 2, 2020 Category: Neurology Source Type: research

Correction to: ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer ’s disease
Unfortunately, the acknowledgement section was not included in the original publication. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - September 26, 2020 Category: Neurology Source Type: research

Mosaic trisomy of chromosome 1q in human brain tissue associates with unilateral polymicrogyria, very early-onset focal epilepsy, and severe developmental delay
AbstractPolymicrogyria (PMG) is a developmental cortical malformation characterized by an excess of small and frustrane gyration and abnormal cortical lamination. PMG frequently associates with seizures. The molecular pathomechanisms underlying PMG development are not yet understood. About 40 genes have been associated with PMG, and small copy number variations have also been described in selected patients. We recently provided evidence that epilepsy-associated structural brain lesions can be classified based on genomic DNA methylation patterns. Here, we analyzed 26 PMG patients employing array-based DNA methylation profil...
Source: Acta Neuropathologica - September 25, 2020 Category: Neurology Source Type: research

Inhibition of Bruton ’s tyrosine kinase interferes with pathogenic B-cell development in inflammatory CNS demyelinating disease
AbstractAnti-CD20-mediated B-cell depletion effectively reduces acute multiple sclerosis (MS) flares. Recent data shows that antibody-mediated extinction of B cells as a lasting immune suppression, harbors the risk of developing humoral deficiencies over time. Accordingly, more selective, durable and reversible B-cell-directed MS therapies are needed. We here tested inhibition of Bruton ’s tyrosine kinase (BTK), an enzyme centrally involved in B-cell receptor signaling, as the most promising approach in this direction. Using mouse models of MS, we determined that evobrutinib, the first BTK inhibiting molecule being d...
Source: Acta Neuropathologica - September 17, 2020 Category: Neurology Source Type: research

Association of probable REM sleep behavior disorder with pathology and years of contact sports play in chronic traumatic encephalopathy
AbstractProbable rapid eye movement (REM) sleep behavior disorder (pRBD) is a synucleinopathy-associated parasomnia in which loss of REM sleep muscle atonia results in motor behavior during REM sleep, including dream enactment. Traumatic brain injury is independently associated with increased risk of pRBD and Lewy body disease, and both pRBD and Lewy body disease are often observed in chronic traumatic encephalopathy (CTE). However, the frequency and pathological substrate of pRBD in CTE have not been formally studied and remain unknown. Of the total sample of 247 men, age at death of 63.1  ± 18.8 ...
Source: Acta Neuropathologica - September 16, 2020 Category: Neurology Source Type: research

Phenotypic diversity in ALS and the role of poly-conformational protein misfolding
AbstractIn many types of familial amyotrophic lateral sclerosis (fALS), mutations cause proteins to gain toxic properties that mediate neurodegenerative processes. It is becoming increasingly clear that the proteins involved in ALS, and those responsible for a host of other neurodegenerative diseases, share many characteristics with a growing number of prion diseases. ALS is a heterogenous disease in which the majority of cases are sporadic in their etiology. Studies investigating the inherited forms of the disease are now beginning to provide evidence that some of this heterogeneity may be due to the existence of distinct...
Source: Acta Neuropathologica - September 14, 2020 Category: Neurology Source Type: research

Molecular characterization of CNS paragangliomas identifies cauda equina paragangliomas as a distinct tumor entity
In this study, we analyzed genome-wide DNA methylation profiles of 57 cauda equina paragangliomas and show that these tumors are epigenetically distinct from non-spinal paragangliomas and other tumors. In contrast to paragangliomas of other sites, chromosomal imbalances are widely lacking in cauda equina paragangliomas. Furthermore, RNA and DNA exome sequencing revealed that frequent genetic alterations found in non-spinal paragangliomas—including the prognostically relevant SDH mutations—are absent in cauda equina paragangliomas. Histologically, cauda equina paragangliomas show frequent ly gangliocytic differe...
Source: Acta Neuropathologica - September 13, 2020 Category: Neurology Source Type: research

The coarse-grained plaque: a divergent A β plaque-type in early-onset Alzheimer’s disease
In this study, we evaluate the plaque’s association with clinical disease and perform in-depth immunohistochemical and morphological characterization. The coarse-grained plaque, a relatively large (Ø ≈ 80 µm) deposit, characterized as having multiple cores and Aβ-devoid pores, was prominent in the neocortex. The plaque was semi-quantitatively scored in the midd le frontal gyrus of Aβ-positive cases (n = 74), including non-demented cases (n = 15), early-onset (EO)AD (n = 38), and late-onset (LO)AD cases (n = 21). Th...
Source: Acta Neuropathologica - September 13, 2020 Category: Neurology Source Type: research

Altered DNA methylation profiles in blood from patients with sporadic Creutzfeldt –Jakob disease
AbstractPrion diseases are fatal and transmissible neurodegenerative disorders caused by the misfolding and aggregation of prion protein. Although recent studies have implicated epigenetic variation in common neurodegenerative disorders, no study has yet explored their role in human prion diseases. Here we profiled genome-wide blood DNA methylation in the most common human prion disease, sporadic Creutzfeldt –Jakob disease (sCJD). Our case–control study (n = 219), when accounting for differences in cell type composition between individuals, identified 38 probes at genome-wide significance (p 
Source: Acta Neuropathologica - September 11, 2020 Category: Neurology Source Type: research

C11orf95-RELA reprograms 3D epigenome in supratentorial ependymoma
AbstractSupratentorial ependymoma (ST-EPN) is a type of malignant brain tumor mainly seen in children. Since 2014, it has been known that an intrachromosomal fusionC11orf95-RELA is an oncogenic driver in ST-EPN [Parker et al. Nature 506:451 –455 (2014); Pietsch et al. Acta Neuropathol 127:609–611 (2014)] but the molecular mechanisms of oncogenesis are unclear. Here we show that the C11orf95 component of the fusion protein dictates DNA binding activity while the RELA component is required for driving the expression of ependymoma-ass ociated genes. Epigenomic characterizations using ChIP-seq and HiChIP approaches...
Source: Acta Neuropathologica - September 8, 2020 Category: Neurology Source Type: research

Germline-driven replication repair-deficient high-grade gliomas exhibit unique hypomethylation patterns
AbstractReplication repair deficiency (RRD) leading to hypermutation is an important driving mechanism of high-grade glioma (HGG) occurring predominantly in the context of germline mutations in RRD-associated genes. Although HGG presents specific patterns of DNA methylation corresponding to oncogenic mutations, this has not been well studied in replication repair-deficient tumors. We analyzed 51 HGG arising in the background of gene mutations in RRD utilizing either 450  k or 850 k methylation arrays. These were compared with HGG not known to be from patients with RRD. RRD HGG harboring secondary mutations in gli...
Source: Acta Neuropathologica - September 7, 2020 Category: Neurology Source Type: research

Extrinsic immune cell-derived, but not intrinsic oligodendroglial factors contribute to oligodendroglial differentiation block in multiple sclerosis
AbstractMultiple sclerosis (MS) is the most frequent demyelinating disease in young adults and despite significant advances in immunotherapy, disease progression still cannot be prevented. Promotion of remyelination, an endogenous repair mechanism resulting in the formation of new myelin sheaths around demyelinated axons, represents a promising new treatment approach. However, remyelination frequently fails in MS lesions, which can in part be attributed to impaired differentiation of oligodendroglial progenitor cells into mature, myelinating oligodendrocytes. The reasons for impaired oligodendroglial differentiation and de...
Source: Acta Neuropathologica - September 6, 2020 Category: Neurology Source Type: research

The immunohistochemical, DNA methylation, and chromosomal copy number profile of cauda equina paraganglioma is distinct from extra-spinal paraganglioma
AbstractParagangliomas are neuroendocrine tumors of the autonomic nervous system that are variably clinically functional and have a potential for metastasis. Up to 40% occur in the setting of a hereditary syndrome, most commonly due to germline mutations in succinate dehydrogenase (SDHx) genes. Immunohistochemically, paragangliomas are characteristically GATA3-positive and cytokeratin-negative, with loss of SDHB expression in most hereditary cases. In contrast, the rare paragangliomas arising in the cauda equina (CEP) or filum terminale region have been shown to be hormonally silent, clinically indolent, and have variable ...
Source: Acta Neuropathologica - September 5, 2020 Category: Neurology Source Type: research

Segregation of ATP10B variants in families with autosomal recessive parkinsonism
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - September 4, 2020 Category: Neurology Source Type: research

Reply: Segregation of ATP10B variants in families with autosomal recessive Parkinsonism
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - September 4, 2020 Category: Neurology Source Type: research

C9orf72 loss-of-function: a trivial, stand-alone or additive mechanism in C9 ALS/FTD?
In conclusion, with evidence pointing to a multiple-hit model, loss-of-function on itself seems to be insufficient to cause neurodegeneration inC9orf72 ALS/FTD. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - September 1, 2020 Category: Neurology Source Type: research

Cerebral blood flow decrease as an early pathological mechanism in Alzheimer's disease
AbstractTherapies targeting late events in Alzheimer ’s disease (AD), including aggregation of amyloid beta (Aβ) and hyperphosphorylated tau, have largely failed, probably because they are given after significant neuronal damage has occurred. Biomarkers suggest that the earliest event in AD is a decrease of cerebral blood flow (CBF). This is caused by constriction of capillaries by contractile pericytes, probably evoked by oligomeric Aβ. CBF is also reduced by neutrophil trapping in capillaries and clot formation, perhaps secondary to the capillary constriction. The fall in CBF potentiates neurodegeneration...
Source: Acta Neuropathologica - August 30, 2020 Category: Neurology Source Type: research

Dipeptide repeat protein and TDP-43 pathology along the hypothalamic –pituitary axis in C9orf72 and non-C9orf72 ALS and FTLD-TDP cases
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - August 29, 2020 Category: Neurology Source Type: research

Correlates of critical illness-related encephalopathy predominate postmortem COVID-19 neuropathology
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - August 25, 2020 Category: Neurology Source Type: research

APOE and TREM2 regulate amyloid-responsive microglia in Alzheimer ’s disease
AbstractBeta-amyloid deposition is a defining feature of Alzheimer ’s disease (AD). How genetic risk factors, likeAPOE andTREM2, intersect with cellular responses to beta-amyloid in human tissues is not fully understood. Using single-nucleus RNA sequencing of postmortem human brain with variedAPOE andTREM2 genotypes and neuropathology, we identified distinct microglia subpopulations, including a subpopulation of CD163-positive amyloid-responsive microglia (ARM) that are depleted in cases withAPOE andTREM2 risk variants. We validated our single-nucleus RNA sequencing findings in an expanded cohort of AD cases, demonst...
Source: Acta Neuropathologica - August 24, 2020 Category: Neurology Source Type: research

Degeneration of the locus coeruleus is a common feature of tauopathies and distinct from TDP-43 proteinopathies in the frontotemporal lobar degeneration spectrum
We examined 280 patients including FTLD-tau (n = 94), FTLD-TDP (n = 135), and two reference groups: clinical/pathological AD (n = 32) and healthy controls (HC,n = 19). Adjacent sections of pons tissue containing the LC were immunostained for phosphorylated TDP-43 (1D3-p409/410), hyperphosphorylated tau (PHF-1), and tyrosine hydroxylase (TH) to examine neuromelanin-containing noradrenergic neurons. Blinded to clinical and pathologic diagnoses, we semi-q uantitatively scored inclusions of tau and TDP-43 both inside LC neuronal somas and in surrounding neuropil. We also ...
Source: Acta Neuropathologica - August 16, 2020 Category: Neurology Source Type: research

TDP-43 transports ribosomal protein mRNA to regulate axonal local translation in neuronal axons
AbstractMislocalization and abnormal deposition of TDP-43 into the cytoplasm (TDP-43 proteinopathy) is a hallmark in neurons of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). However, the pathogenic mechanism of the diseases linked to TDP-43 is largely unknown. We hypothesized that the failure of mRNA transport to neuronal axons by TDP-43 may contribute to neurodegeneration in ALS and FTLD, and sought to examine the function of TDP-43 by identifying its target mRNA for axonal transport. We found that mRNAs related to translational function including ribosomal proteins (RPs) were decreased...
Source: Acta Neuropathologica - August 15, 2020 Category: Neurology Source Type: research

Distinct clinicopathologic clusters of persons with TDP-43 proteinopathy
AbstractTo better understand clinical and neuropathological features of TDP-43 proteinopathies, data were analyzed from autopsied research volunteers who were followed in the National Alzheimer ’s Coordinating Center (NACC) data set. All subjects (n = 495) had autopsy-proven TDP-43 proteinopathy as an inclusion criterion. Subjects underwent comprehensive longitudinal clinical evaluations yearly for 6.9 years before death on average. We tested whether an unsupervised clustering algorithm could detect coherent groups of TDP-43 immunopositiv e cases based on age at death and extensive neuropathologic ...
Source: Acta Neuropathologica - August 13, 2020 Category: Neurology Source Type: research

Brain pathologies are associated with both the rate and variability of declining motor function in older adults
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - August 13, 2020 Category: Neurology Source Type: research

Characterizing tau deposition in chronic traumatic encephalopathy (CTE): utility of the McKee CTE staging scheme
The objective of this study was to test the utility of the McKee CTE staging scheme, and provide a detailed examination of the regional distribution of p-tau in CTE. We examined the relationship between the McKee CTE staging sche me and semi-quantitative and quantitative assessments of regional p-tau pathology, age at death, dementia, and years of American football play among 366 male brain donors neuropathologically diagnosed with CTE (mean age 61.86, SD 18.90). Spearman’s rho correlations showed that higher CTE stage was associated with higher scores on all semi-quantitative and quantitative assessments of p-t...
Source: Acta Neuropathologica - August 10, 2020 Category: Neurology Source Type: research

Antibody against TDP-43 phosphorylated at serine 375 suggests conformational differences of TDP-43 aggregates among FTLD –TDP subtypes
AbstractAggregation of hyperphosphorylated TDP-43 is the hallmark pathological feature of the most common molecular form of frontotemporal lobar degeneration (FTLD –TDP) and in the vast majority of cases with amyotrophic lateral sclerosis (ALS–TDP). However, most of the specific phosphorylation sites remain to be determined, and their relevance regarding pathogenicity and clinical and pathological phenotypic diversity in FTLD–TDP and ALS–TDP remains to be identified. Here, we generated a novel antibody raised against TDP-43 phosphorylated at serine 375 (pTDP-43S375) located in the low-complexity dom...
Source: Acta Neuropathologica - August 9, 2020 Category: Neurology Source Type: research

Infratentorial IDH-mutant astrocytoma is a distinct subtype
We report that about 80% of IDH mutations in these tumors are of non-IDH1-R132H variants which are rare in supratentorial astrocytomas. Most frequently, IDH1-R132C/G and IDH2-R172S/G mutations were present. Moreover, the frequencies of ATRX-loss andMGMT promoter methylation, which are typically associated with IDH mutations in supratentorial astrocytic tumors, were significantly lower in the infratentorial compartment. Gene panel sequencing revealed two samples with IDH1-R132C/H3F3A-K27M co-mutations. Genome-wide DNA methylation as well as chromosomal copy number profiling provided further evidence for a molecular distinct...
Source: Acta Neuropathologica - August 9, 2020 Category: Neurology Source Type: research

TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis
AbstractMultiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS) triggered by autoimmune mechanisms. Microglia are critical for the clearance of myelin debris in areas of demyelination, a key step to allow remyelination. TREM2 is expressed by microglia and promotes microglial survival, proliferation, and phagocytic activity. Herein we demonstrate that TREM2 was highly expressed on myelin-laden phagocytes in active demyelinating lesions in the CNS of subjects with MS. In gene expression studies, macrophages from subjects with TREM2 genetic deficiency displa...
Source: Acta Neuropathologica - August 8, 2020 Category: Neurology Source Type: research

Post-mortem analyses of PiB and flutemetamol in diffuse and cored amyloid- β plaques in Alzheimer’s disease
AbstractSpecificity and sensitivity of positron emission tomography (PET) radiopharmaceuticals targeting fibrillar amyloid- β (Aβ) deposits is high for detection of neuritic Aβ plaques, a mature form of Aβ deposits which often have dense Aβ core (i.e., cored plaques). However, imaging-to-autopsy validation studies of amyloid PET radioligands have identified several false positive cases all of which had mainly diffus e Aβ plaques (i.e., plaques without neuritic pathology or dense amyloid core), and high amyloid PET signal was reported in the striatum where diffuse plaques predominate in Alzheim...
Source: Acta Neuropathologica - August 8, 2020 Category: Neurology Source Type: research

WNT-activated embryonal tumors of the pineal region: ectopic medulloblastomas or a novel pineoblastoma subgroup?
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - August 7, 2020 Category: Neurology Source Type: research

ADNC-RS, a clinical-genetic risk score, predicts Alzheimer ’s pathology in autopsy-confirmed Parkinson’s disease and Dementia with Lewy bodies
AbstractGrowing evidence suggests overlap between Alzheimer ’s disease (AD) and Parkinson’s disease (PD) pathophysiology in a subset of patients. Indeed, 50–80% of autopsy cases with a primary clinicopathological diagnosis of Lewy body disease (LBD)—most commonly manifesting during life as PD—have concomitant amyloid-beta and tau pathology, the def ining pathologies of AD. Here we evaluated common genetic variants in genome-wide association with AD as predictors of concomitant AD pathology in the brains of people with a primary clinicopathological diagnosis of PD or Dementia with Lewy Bodies (...
Source: Acta Neuropathologica - August 3, 2020 Category: Neurology Source Type: research

The role of hnRNPs in frontotemporal dementia and amyotrophic lateral sclerosis
AbstractDysregulated RNA metabolism is emerging as a crucially important mechanism underpinning the pathogenesis of frontotemporal dementia (FTD) and the clinically, genetically and pathologically overlapping disorder of amyotrophic lateral sclerosis (ALS). Heterogeneous nuclear ribonucleoproteins (hnRNPs) comprise a family of RNA-binding proteins with diverse, multi-functional roles across all aspects of mRNA processing. The role of these proteins in neurodegeneration is far from understood. Here, we review some of the unifying mechanisms by which hnRNPs have been directly or indirectly linked with FTD/ALS pathogenesis, i...
Source: Acta Neuropathologica - August 2, 2020 Category: Neurology Source Type: research