Antisense RNA foci in the motor neurons of C9ORF72 -ALS patients are associated with TDP-43 proteinopathy
Abstract GGGGCC repeat expansions of C9ORF72 represent the most common genetic variant of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We and others have proposed that RNA transcribed from the repeat sequence is toxic via sequestration of RNA-binding factors. Both GGGGCC-repeat (sense) and CCCCGG-repeat (antisense) molecules are detectable by fluorescence in situ hybridisation as RNA foci, but their relative expression pattern within the CNS and contribution to disease has not been determined. Blinded examination of CNS biosamples from ALS patients with a repeat expansion of C9ORF72 showed that...
Source: Acta Neuropathologica - May 6, 2015 Category: Neurology Source Type: research

Glioblastoma: pathology, molecular mechanisms and markers
Abstract Recent advances in genomic technology have led to a better understanding of key molecular alterations that underlie glioblastoma (GBM). The current WHO-based classification of GBM is mainly based on histologic features of the tumor, which frequently do not reflect the molecular differences that describe the diversity in the biology of these lesions. The current WHO definition of GBM relies on the presence of high-grade astrocytic neoplasm with the presence of either microvascular proliferation and/or tumor necrosis. High-throughput analyses have identified molecular subtypes and have led to progress in mo...
Source: Acta Neuropathologica - May 6, 2015 Category: Neurology Source Type: research

Pediatric atypical choroid plexus papilloma reconsidered: increased mitotic activity is prognostic only in older children
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 2, 2015 Category: Neurology Source Type: research

Zebrafish models for nemaline myopathy reveal a spectrum of nemaline bodies contributing to reduced muscle function
Abstract Nemaline myopathy is characterized by muscle weakness and the presence of rod-like (nemaline) bodies. The genetic etiology of nemaline myopathy is becoming increasingly understood with mutations in ten genes now known to cause the disease. Despite this, the mechanism by which skeletal muscle weakness occurs remains elusive, with previous studies showing no correlation between the frequency of nemaline bodies and disease severity. To investigate the formation of nemaline bodies and their role in pathogenesis, we generated overexpression and loss-of-function zebrafish models for skeletal muscle α-acti...
Source: Acta Neuropathologica - May 1, 2015 Category: Neurology Source Type: research

Molecular profiling of long-term survivors identifies a subgroup of glioblastoma characterized by chromosome 19/20 co-gain
In conclusion, these findings provide important insights into the manipulation of the innate immune system by particularly aggressive GBM tumors. Furthermore, we genomically characterize a previously unknown, clinically relevant subgroup of glioblastoma, which can easily be identified through modern neuropathological workup. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 1, 2015 Category: Neurology Source Type: research

Erratum to: Sequential distribution of pTDP-43 pathology in behavioral variant frontotemporal dementia (bvFTD)
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 1, 2015 Category: Neurology Source Type: research

Fumarates modulate microglia activation through a novel HCAR2 signaling pathway and rescue synaptic dysregulation in inflamed CNS
Abstract Dimethyl fumarate (DMF), recently approved as an oral immunomodulatory treatment for relapsing-remitting multiple sclerosis (MS), metabolizes to monomethyl fumarate (MMF) which crosses the blood–brain barrier and has demonstrated neuroprotective effects in experimental studies. We postulated that MMF exerts neuroprotective effects through modulation of microglia activation, a critical component of the neuroinflammatory cascade that occurs in neurodegenerative diseases such as MS. To ascertain our hypothesis and define the mechanistic pathways involved in the modulating effect of fumarates, we used r...
Source: Acta Neuropathologica - April 29, 2015 Category: Neurology Source Type: research

A truncating SOD1 mutation, p.Gly141X, is associated with clinical and pathologic heterogeneity, including frontotemporal lobar degeneration
We report clinical and pathologic findings of a family with ALS due to a truncating mutation, p.Gly141X, in copper/zinc superoxide dismutase (SOD1). The proband presented clinically with FTD and later showed progressive motor neuron disease, while all other family members had early-onset and rapidly progressive ALS without significant cognitive deficits. Pathologic examination of both the proband and her daughter revealed degeneration of corticospinal tracts and motor neurons in brain and spinal cord compatible with ALS. On the other hand, the proband also had neocortical and limbic system degeneration with pleomorphic neu...
Source: Acta Neuropathologica - April 28, 2015 Category: Neurology Source Type: research

A novel tau mutation, p.K317N, causes globular glial tauopathy
In this report, six patients with GGT (four with subtype III and two with subtype I) were screened for MAPT mutations. They included 4 men and 2 women with a mean age at death of 73 years (55–83 years) and mean age at symptomatic onset of 66 years (50–77 years). Disease duration ranged from 5 to 14 years. All were homozygous for the MAPT H1 haplotype. Three patients had a positive family history of dementia, and a novel MAPT mutation (c.951G>C, p.K317N) was identified in one of them, a patient with subtype III. Recombinant tau protein bearing the lysine-to-asparagine substitution at ...
Source: Acta Neuropathologica - April 22, 2015 Category: Neurology Source Type: research

Primary leptomeningeal melanoma is part of the BAP1 -related cancer syndrome
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - April 22, 2015 Category: Neurology Source Type: research

Extracellular association of APP and tau fibrils induces intracellular aggregate formation of tau
In this study, we investigated whether expression of amyloid precursor protein (APP) influences extracellular seed-dependent intracellular tau accumulation in cultured cells. Treatment of tau-expressing SH-SY5Y cells with Aβ fibrils did not induce intracellular tau aggregation. On the other hand, in cells expressing both tau and APP, treatment with tau fibrils or Sarkosyl-insoluble tau from AD brains induced intracellular tau aggregation. The seed-dependent intracellular tau aggregation was not induced by expression of APP lacking the extracellular domain. The amount of phosphorylated tau aggregates in cultured cells ...
Source: Acta Neuropathologica - April 14, 2015 Category: Neurology Source Type: research

Induction of endogenous Type I interferon within the central nervous system plays a protective role in experimental autoimmune encephalomyelitis
Abstract The Type I interferons (IFN), beta (IFN-β) and the alpha family (IFN-α), act through a common receptor and have anti-inflammatory effects. IFN-β is used to treat multiple sclerosis (MS) and is effective against experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Mice with EAE show elevated levels of Type I IFNs in the central nervous system (CNS), suggesting a role for endogenous Type I IFN during inflammation. However, the therapeutic benefit of Type I IFN produced in the CNS remains to be established. The aim of this study was to examine whether experimentally induce...
Source: Acta Neuropathologica - April 14, 2015 Category: Neurology Source Type: research

Intraneuronal APP and extracellular Aβ independently cause dendritic spine pathology in transgenic mouse models of Alzheimer’s disease
Abstract Alzheimer’s disease (AD) is thought to be caused by accumulation of amyloid-β protein (Aβ), which is a cleavage product of amyloid precursor protein (APP). Transgenic mice overexpressing APP have been used to recapitulate amyloid-β pathology. Among them, APP23 and APPswe/PS1deltaE9 (deltaE9) mice are extensively studied. APP23 mice express APP with Swedish mutation and develop amyloid plaques late in their life, while cognitive deficits are observed in young age. In contrast, deltaE9 mice with mutant APP and mutant presenilin-1 develop amyloid plaques early but show typical cognitive ...
Source: Acta Neuropathologica - April 11, 2015 Category: Neurology Source Type: research

Aβ 43 is neurotoxic and primes aggregation of Aβ 40 in vivo
Abstract The involvement of Amyloid-β (Aβ) in the pathogenesis of Alzheimer’s disease (AD) is well established. However, it is becoming clear that the amyloid load in AD brains consists of a heterogeneous mixture of Aβ peptides, implying that a thorough understanding of their respective role and toxicity is crucial for the development of efficient treatments. Besides the well-studied Aβ40 and Aβ42 species, recent data have raised the possibility that Aβ43 peptides might be instrumental in AD pathogenesis, because they are frequently observed in both dense and diffuse amyloid pla...
Source: Acta Neuropathologica - April 11, 2015 Category: Neurology Source Type: research

Identification of a novel MET mutation in high-grade glioma resulting in an auto-active intracellular protein
Abstract MET has gained interest as a therapeutic target for a number of malignancies because of its involvement in tumorigenesis, invasion and metastasis. At present, a number of inhibitors, both antibodies against MET or its ligand hepatocyte growth factor, and small molecule MET tyrosine kinase inhibitors are in clinical trials. We here describe a novel variant of MET that is expressed in 6 % of high-grade gliomas. Characterization of this mutation in a glioma cell line revealed that it consists of an intronic deletion, resulting in a splice event connecting an intact splice donor site in exon 6 with the n...
Source: Acta Neuropathologica - April 11, 2015 Category: Neurology Source Type: research

Templated misfolding of Tau by prion-like seeding along neuronal connections impairs neuronal network function and associated behavioral outcomes in Tau transgenic mice
Abstract Prion-like seeding and propagation of Tau-pathology have been demonstrated experimentally and may underlie the stereotyped progression of neurodegenerative Tauopathies. However, the involvement of templated misfolding of Tau in neuronal network dysfunction and behavioral outcomes remains to be explored in detail. Here we analyzed the repercussions of prion-like spreading of Tau-pathology via neuronal connections on neuronal network function in TauP301S transgenic mice. Spontaneous and GABAAR-antagonist-induced neuronal network activity were affected following templated Tau-misfolding using synthetic prefo...
Source: Acta Neuropathologica - April 11, 2015 Category: Neurology Source Type: research

Soluble VCAM-1 impairs human brain endothelial barrier integrity via integrin α-4-transduced outside-in signalling
Abstract Human brain microvascular endothelial cells forming the blood–brain barrier (BBB) release soluble vascular cell adhesion molecule-1 (sVCAM-1) under inflammatory conditions. Furthermore, sVCAM-1 serum levels in untreated patients with multiple sclerosis (MS) correlate with a breakdown of the BBB as measured by gadolinium-enhanced MRI. To date, it is unknown whether sVCAM-1 itself modulates BBB permeability. Here, we provide evidence that human brain endothelium expresses integrin α-4/β-1, the molecular binding partner of sVCAM-1, and that sVCAM-1 directly impairs BBB function by inducing i...
Source: Acta Neuropathologica - March 27, 2015 Category: Neurology Source Type: research

Does the difference between PART and Alzheimer’s disease lie in the age-related changes in cerebral arteries that trigger the accumulation of Aβ and propagation of tau?
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 27, 2015 Category: Neurology Source Type: research

Acknowledgement to referees
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 20, 2015 Category: Neurology Source Type: research

Pilocytic astrocytoma: pathology, molecular mechanisms and markers
Abstract Pilocytic astrocytomas (PAs) were recognized as a discrete clinical entity over 70 years ago. They are relatively benign (WHO grade I) and have, as a group, a 10-year survival of over 90 %. Many require merely surgical removal and only very infrequently do they progress to more malignant gliomas. While most show classical morphology, they may present a spectrum of morphological patterns, and there are difficult cases that show similarities to other gliomas, some of which are malignant and require aggressive treatment. Until recently, almost nothing was known about the molecular mechanisms involv...
Source: Acta Neuropathologica - March 20, 2015 Category: Neurology Source Type: research

Low molecular weight species of TDP-43 generated by abnormal splicing form inclusions in amyotrophic lateral sclerosis and result in motor neuron death
Abstract The presence of lower molecular weight species comprising the C-terminal region of TAR DNA-binding protein 43 (TDP-43) is a characteristic of TDP-43 proteinopathy in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here, we have identified a novel splice variant of TDP-43 that is upregulated in ALS and generates a 35-kDa N-terminally truncated species through use of an alternate translation initiation codon (ATGMet85), denoted here as Met85-TDP-35. Met85-TDP-35 expressed ectopically in human neuroblastoma cells exhibited reduced solubility, cytoplasmic distribution, and ag...
Source: Acta Neuropathologica - March 19, 2015 Category: Neurology Source Type: research

Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups
Abstract Cerebral gliomas of World Health Organization (WHO) grade II and III represent a major challenge in terms of histological classification and clinical management. Here, we asked whether large-scale genomic and transcriptomic profiling improves the definition of prognostically distinct entities. We performed microarray-based genome- and transcriptome-wide analyses of primary tumor samples from a prospective German Glioma Network cohort of 137 patients with cerebral gliomas, including 61 WHO grade II and 76 WHO grade III tumors. Integrative bioinformatic analyses were employed to define molecular subgrou...
Source: Acta Neuropathologica - March 18, 2015 Category: Neurology Source Type: research

Extracellular vesicle sorting of α-Synuclein is regulated by sumoylation
Abstract Extracellular α-Synuclein has been implicated in interneuronal propagation of disease pathology in Parkinson’s Disease. How α-Synuclein is released into the extracellular space is still unclear. Here, we show that α-Synuclein is present in extracellular vesicles in the central nervous system. We find that sorting of α-Synuclein in extracellular vesicles is regulated by sumoylation and that sumoylation acts as a sorting factor for targeting of both, cytosolic and transmembrane proteins, to extracellular vesicles. We provide evidence that the SUMO-dependent sorting utilizes the...
Source: Acta Neuropathologica - March 17, 2015 Category: Neurology Source Type: research

Alterations of mGluR5 and its endogenous regulators Norbin, Tamalin and Preso1 in schizophrenia: towards a model of mGluR5 dysregulation
Abstract Knockout of genes encoding metabotropic glutamate receptor 5 (mGluR5) or its endogenous regulators, such as Norbin, induce a schizophrenia-like phenotype in rodents, suggesting dysregulation of mGluR5 in schizophrenia. Human genetic and pharmacological animal studies support this hypothesis, but no studies have explored mGluR5 dysfunction at the molecular level in the postmortem schizophrenia brain. We assessed mGluR5 mRNA and protein levels in the dorsolateral prefrontal cortex (DLPFC) using a large cohort of schizophrenia and control subjects (n = 37/group), and additionally measured protein l...
Source: Acta Neuropathologica - March 17, 2015 Category: Neurology Source Type: research

PART, a distinct tauopathy, different from classical sporadic Alzheimer disease
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 17, 2015 Category: Neurology Source Type: research

M. leprae components induce nerve damage by complement activation: identification of lipoarabinomannan as the dominant complement activator
Abstract Peripheral nerve damage is the hallmark of leprosy pathology but its etiology is unclear. We previously identified the membrane attack complex (MAC) of the complement system as a key determinant of post-traumatic nerve damage and demonstrated that its inhibition is neuroprotective. Here, we determined the contribution of the MAC to nerve damage caused by Mycobacterium leprae and its components in mouse. Furthermore, we studied the association between MAC and the key M. leprae component lipoarabinomannan (LAM) in nerve biopsies of leprosy patients. Intraneural injections of M. leprae sonicate induced MAC d...
Source: Acta Neuropathologica - March 14, 2015 Category: Neurology Source Type: research

Neuropathologically mixed Alzheimer’s and Lewy body disease: burden of pathological protein aggregates differs between clinical phenotypes
Abstract Multiple different pathological protein aggregates are frequently seen in human postmortem brains and hence mixed pathology is common. Mixed dementia on the other hand is less frequent and neuropathologically should only be diagnosed if criteria for more than one full blown disease are met. We quantitatively measured the amount of hyperphosphorylated microtubule associated tau (HP-τ), amyloid-β protein (Aβ) and α-synuclein (α-syn) in cases that were neuropathologically diagnosed as mixed Alzheimer’s disease (AD) and neocortical Lewy body disease (LBD) but clinically pr...
Source: Acta Neuropathologica - March 11, 2015 Category: Neurology Source Type: research

Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers
Abstract Pediatric glioblastoma (pedGBM) is amongst the most common malignant brain tumors of childhood and carries a dismal prognosis. In contrast to adult GBM, few molecular prognostic markers for the pediatric counterpart have been established. We, therefore, investigated the prognostic significance of genomic and epigenetic alterations through molecular analysis of 202 pedGBM (1–18 years) with comprehensive clinical annotation. Routinely prepared formalin-fixed paraffin-embedded tumor samples were assessed for genome-wide DNA methylation profiles, with known candidate genes screened for alterations ...
Source: Acta Neuropathologica - March 10, 2015 Category: Neurology Source Type: research

Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment
Abstract Temozolomide (TMZ) increases the overall survival of patients with glioblastoma (GBM), but its role in the clinical management of diffuse low-grade gliomas (LGG) is still being defined. DNA hypermethylation of the O 6 -methylguanine-DNA methyltransferase (MGMT) promoter is associated with an improved response to TMZ treatment, while inactivation of the DNA mismatch repair (MMR) pathway is associated with therapeutic resistance and TMZ-induced mutagenesis. We previously demonstrated that TMZ treatment of LGG induces driver mutations in the RB and AKT–mTOR pathways, whi...
Source: Acta Neuropathologica - February 27, 2015 Category: Neurology Source Type: research

Liquid biopsies in patients with diffuse glioma
Abstract Diffuse gliomas are the most common malignant primary tumors of the central nervous system. Like other neoplasms, these gliomas release molecular information into the circulation. Tumor-derived biomarkers include proteins, nucleic acids, and tumor-derived extracellular vesicles that accumulate in plasma, serum, blood platelets, urine and/or cerebrospinal fluid. Recently, also circulating tumor cells have been identified in the blood of glioma patients. Circulating molecules, vesicles, platelets, and cells may be useful as easily accessible diagnostic, prognostic and/or predictive biomarkers to guide patie...
Source: Acta Neuropathologica - February 27, 2015 Category: Neurology Source Type: research

High rate of concurrent BRAF - KIAA1549 gene fusion and 1p deletion in disseminated oligodendroglioma-like leptomeningeal neoplasms (DOLN)
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - February 27, 2015 Category: Neurology Source Type: research

The role of IL-17 in CNS diseases
Abstract Cytokines of the IL-17 family are uniquely placed on the border between immune cells and tissue. Although IL-17 was originally found to induce the activation and mobilization of neutrophils to sites of inflammation, its tissue-specific function is not yet fully understood. The best-studied IL-17 family members, IL-17A and IL-17F, are both typically produced by immune cells such as Th17, γδ T cells and innate lymphoid cells group 3. However, the cells that respond to these cytokines are mostly found in inflamed tissue. As seen in psoriatic skin lesions or in joints of rheumatoid arthritis patie...
Source: Acta Neuropathologica - February 26, 2015 Category: Neurology Source Type: research

The C9orf72 repeat expansion itself is methylated in ALS and FTLD patients
Abstract The most common cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) is a G4C2-repeat expansion in C9orf72. However, the lower limit for pathological repeats has not been established and expansions with different sizes could have different pathological consequences. One of the implicated disease mechanisms is haploinsufficiency. Previously, we identified expansion-specific hypermethylation at the 5′ CpG-island near the G4C2-repeat, but only in a fraction of carriers (up to 36 %). Here, we tested the hypothesis that the G4C2-repeat itself could be the ma...
Source: Acta Neuropathologica - February 26, 2015 Category: Neurology Source Type: research

IDH mutation status and role of WHO grade and mitotic index in overall survival in grade II–III diffuse gliomas
Abstract Diffuse gliomas are up till now graded based upon morphology. Recent findings indicate that isocitrate dehydrogenase (IDH) mutation status defines biologically distinct groups of tumors. The role of tumor grade and mitotic index in patient outcome has not been evaluated following stratification by IDH mutation status. To address this, we interrogated 558 WHO grade II–III diffuse gliomas for IDH1/2 mutations and investigated the prognostic impact of WHO grade within IDH-mutant and IDH-wild type tumor subsets independently. The prognostic impact of grade was modest in IDH-mutant [hazard ratio (HR)&nbs...
Source: Acta Neuropathologica - February 21, 2015 Category: Neurology Source Type: research

Critical role of somatostatin receptor 2 in the vulnerability of the central noradrenergic system: new aspects on Alzheimer’s disease
Abstract Alzheimer’s disease and other age-related neurodegenerative disorders are associated with deterioration of the noradrenergic locus coeruleus (LC), a probable trigger for mood and memory dysfunction. LC noradrenergic neurons exhibit particularly high levels of somatostatin binding sites. This is noteworthy since cortical and hypothalamic somatostatin content is reduced in neurodegenerative pathologies. Yet a possible role of a somatostatin signal deficit in the maintenance of noradrenergic projections remains unknown. Here, we deployed tissue microarrays, immunohistochemistry, quantitative morphometr...
Source: Acta Neuropathologica - February 13, 2015 Category: Neurology Source Type: research

Isoglutaminyl cyclase contributes to CCL2-driven neuroinflammation in Alzheimer’s disease
Abstract The brains of Alzheimer’s disease (AD) patients are characterized by deposits of Abeta peptides and by accompanying chronic inflammation. Here, we provide evidence that the enzyme isoglutaminyl cyclase (isoQC) is a novel factor contributing to both aspects of AD pathology. Two putative substrates of isoQC, N-truncated Abeta peptides and the monocyte chemoattractant chemokine CCL2, undergo isoQC-catalyzed pyroglutamate (pGlu) modification. This triggers Abeta aggregation and facilitates the biological activity of CCL2, which collectively results in the formation of high molecular weight Abeta aggrega...
Source: Acta Neuropathologica - February 11, 2015 Category: Neurology Source Type: research

Histological subtype of medulloblastoma frequently changes upon recurrence
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - February 7, 2015 Category: Neurology Source Type: research

Autophagy in neuropathology
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - February 4, 2015 Category: Neurology Source Type: research

X-linked myopathy with excessive autophagy: a failure of self-eating
Abstract Autophagic vacuolar myopathies (AVMs) are a group of disorders united by shared histopathological features on muscle biopsy that include the aberrant accumulation of autophagic vacuoles. The classic conditions that compose the AVMs include Pompe Disease, Danon Disease and X-linked myopathy with excessive autophagy (XMEA). Other disorders, including acquired myopathies like chloroquine toxicity, also have features of an autophagic myopathy. This review is focused on XMEA, a myopathy with onset of slowly progressive proximal weakness and elevated serum creatine kinase (2× to 20× normal...
Source: Acta Neuropathologica - February 3, 2015 Category: Neurology Source Type: research

Nucleus basalis of Meynert revisited: anatomy, history and differential involvement in Alzheimer’s and Parkinson’s disease
Abstract It has been well established that neuronal loss within the cholinergic nucleus basalis of Meynert (nbM) correlates with cognitive decline in dementing disorders such as Alzheimer’s disease (AD). Friedrich Lewy first observed his eponymous inclusion bodies in the nbM of postmortem brain tissue from patients with Parkinson’s disease (PD) and cell loss in this area can be at least as extensive as that seen in AD. There has been confusion with regard to the terminology and exact localisation of the nbM within the human basal forebrain for decades due to the diffuse and broad structure of this &ldq...
Source: Acta Neuropathologica - January 30, 2015 Category: Neurology Source Type: research

TREM2 regulates microglial cell activation in response to demyelination in vivo
Abstract Microglia are phagocytic cells that survey the brain and perform neuroprotective functions in response to tissue damage, but their activating receptors are largely unknown. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immunoreceptor whose loss-of-function mutations in humans cause presenile dementia, while genetic variants are associated with increased risk of neurodegenerative diseases. In myeloid cells, TREM2 has been involved in the regulation of phagocytosis, cell proliferation and inflammatory responses in vitro. However, it is unknown how TREM2 contributes to microglia fu...
Source: Acta Neuropathologica - January 29, 2015 Category: Neurology Source Type: research

PART is part of Alzheimer disease
Abstract It has been proposed that tau aggregation confined to entorhinal cortex and hippocampus, with no or only minimal Aβ deposition, should be considered as a ‘primary age-related tauopathy’ (PART) that is not integral to the continuum of sporadic Alzheimer disease (AD). Here, we examine the evidence that PART has a pathogenic mechanism and a prognosis which differ from those of AD. We contend that no specific property of the entorhinal–hippocampal tau pathology makes it possible to predict either a limited progression or the development of AD, and that biochemical differences await an e...
Source: Acta Neuropathologica - January 28, 2015 Category: Neurology Source Type: research

Physiological and pathophysiological functions of cell cycle proteins in post-mitotic neurons: implications for Alzheimer’s disease
Abstract Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder for which no effective treatment is available. Increased insight into the disease mechanism in early stages of pathology is required for the development of a successful therapy. Over the years, numerous studies have shown that cell cycle proteins are expressed in neurons of AD patients. Traditionally, neurons are considered to be post-mitotic, which means that they permanently retract from the cell cycle. The expression of cell cycle proteins in adult neurons of AD patients has therefore been suggested to promote or even insti...
Source: Acta Neuropathologica - January 25, 2015 Category: Neurology Source Type: research

Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis
Abstract Protein aggregation is common to dozens of diseases including prionoses, diabetes, Parkinson’s and Alzheimer’s. Over the past 15 years, there has been a paradigm shift in understanding the structural basis for these proteinopathies. Precedent for this shift has come from investigation of soluble Aβ oligomers (AβOs), toxins now widely regarded as instigating neuron damage leading to Alzheimer’s dementia. Toxic AβOs accumulate in AD brain and constitute long-lived alternatives to the disease-defining Aβ fibrils deposited in amyloid plaques. Key experiments using fi...
Source: Acta Neuropathologica - January 22, 2015 Category: Neurology Source Type: research

High CCR5 expression in natalizumab-associated progressive multifocal leukoencephalopathy immune reconstitution inflammatory syndrome supports treatment with the CCR5 inhibitor maraviroc
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - January 22, 2015 Category: Neurology Source Type: research

Medulloblastoma subgroups remain stable across primary and metastatic compartments
Abstract Medulloblastoma comprises four distinct molecular variants with distinct genetics, transcriptomes, and outcomes. Subgroup affiliation has been previously shown to remain stable at the time of recurrence, which likely reflects their distinct cells of origin. However, a therapeutically relevant question that remains unanswered is subgroup stability in the metastatic compartment. We assembled a cohort of 12-paired primary-metastatic tumors collected in the MAGIC consortium, and established their molecular subgroup affiliation by performing integrative gene expression and DNA methylation analysis. Frozen tiss...
Source: Acta Neuropathologica - January 21, 2015 Category: Neurology Source Type: research

Protein aggregation in Alzheimer’s disease: Aβ and τ and their potential roles in the pathogenesis of AD
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - January 20, 2015 Category: Neurology Source Type: research

Danon disease: a phenotypic expression of LAMP-2 deficiency
Abstract Danon disease is an X-linked disorder clinically characterized by the triad of hypertrophic cardiomyopathy, myopathy, and intellectual disability. Cardiomyopathy is a severe and life-threatening problem, for which cardiac transplantation is the only therapeutic option. The most striking finding in muscle biopsy samples is small basophilic granules scattered in myofibers, which are in fact small autophagic vacuoles surrounded by membranes with sarcolemmal features characterized by the recruitment of sarcolemmal proteins and acetylcholine esterase and by the presence of basal lamina on its luminal side. The...
Source: Acta Neuropathologica - January 15, 2015 Category: Neurology Source Type: research

Therapeutic use of CCR5 antagonists is supported by strong expression of CCR5 on CD8 + T cells in progressive multifocal leukoencephalopathy-associated immune reconstitution inflammatory syndrome
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - January 15, 2015 Category: Neurology Source Type: research

Amyloid deposits and inflammatory infiltrates in sporadic inclusion body myositis: the inflammatory egg comes before the degenerative chicken
Abstract Sporadic inclusion body myositis (sIBM) is the most frequently acquired myopathy in patients over 50 years of age. It is imperative that neurologists and rheumatologists recognize this disorder which may, through clinical and pathological similarities, mimic other myopathies, especially polymyositis. Whereas polymyositis responds to immunosuppressant drug therapy, sIBM responds poorly, if at all. Controversy reigns as to whether sIBM is primarily an inflammatory or a degenerative myopathy, the distinction being vitally important in terms of directing research for effective specific therapies. We revi...
Source: Acta Neuropathologica - January 13, 2015 Category: Neurology Source Type: research