C9orf72 FTLD/ALS-associated Gly-Ala dipeptide repeat proteins cause neuronal toxicity and Unc119 sequestration
Abstract Hexanucleotide repeat expansion in C9orf72 is the most common pathogenic mutation in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite the lack of an ATG start codon, the repeat expansion is translated in all reading frames into dipeptide repeat (DPR) proteins, which form insoluble, ubiquitinated, p62-positive aggregates that are most abundant in the cerebral cortex and cerebellum. To specifically analyze DPR toxicity and aggregation, we expressed DPR proteins from synthetic genes containing a start codon but lacking extensive GGGGCC repeats. Poly-Gly...
Source: Acta Neuropathologica - September 25, 2014 Category: Neurology Source Type: research

C9orf72 hypermethylation protects against repeat expansion-associated pathology in ALS/FTD
Abstract Hexanucleotide repeat expansions of C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal degeneration. The mutation is associated with reduced C9orf72 expression and the accumulation of potentially toxic RNA and protein aggregates. CpG methylation is known to protect the genome against unstable DNA elements and to stably silence inappropriate gene expression. Using bisulfite cloning and restriction enzyme-based methylation assays on DNA from human brain and peripheral blood, we observed CpG hypermethylation involving the C9orf72 promoter in cis to the repeat e...
Source: Acta Neuropathologica - September 25, 2014 Category: Neurology Source Type: research

Histopathological spectrum of paediatric diffuse intrinsic pontine glioma: diagnostic and therapeutic implications
Abstract Diffuse intrinsic pontine glioma (DIPG) is the main cause of brain tumour-related death in children. In the majority of cases diagnosis is based on clinical and MRI findings, resulting in the scarcity of pre-treatment specimens available to study. Our group has developed an autopsy-based protocol to investigate the histologic and biologic spectrum of DIPG. This has also allowed us to investigate the terminal pattern of disease and gain a better understanding of what challenges we are facing in treating DIPG. Here, we review 72 DIPG cases with well documented clinical history and molecular data and descri...
Source: Acta Neuropathologica - September 25, 2014 Category: Neurology Source Type: research

Integrated DNA methylation and copy-number profiling identify three clinically and biologically relevant groups of anaplastic glioma
Abstract The outcome of patients with anaplastic gliomas varies considerably. Whether a molecular classification of anaplastic gliomas based on large-scale genomic or epigenomic analyses is superior to histopathology for reflecting distinct biological groups, predicting outcomes and guiding therapy decisions has yet to be determined. Epigenome-wide DNA methylation analysis, using a platform which also allows the detection of copy-number aberrations, was performed in a cohort of 228 patients with anaplastic gliomas (astrocytomas, oligoastrocytomas, and oligodendrogliomas), including 115 patients of the NOA-04 ...
Source: Acta Neuropathologica - September 25, 2014 Category: Neurology Source Type: research

Germ-line and somatic DICER1 mutations in pineoblastoma
This study suggests that germ-line DICER1 mutations make a clinically significant contribution to PinB, establishing DICER1 as an important susceptibility gene for PinB and demonstrates PinB to be a manifestation of a germ-line DICER1 mutation. The means by which the second allele is inactivated may differ from other DICER1-related tumours. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - September 25, 2014 Category: Neurology Source Type: research

Subventricular spread of diffuse intrinsic pontine glioma
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - September 25, 2014 Category: Neurology Source Type: research

A comparison of Aβ amyloid pathology staging systems and correlation with clinical diagnosis
Abstract Current neuropathological Alzheimer’s disease (AD) criteria from the National Institute on Aging-Alzheimer’s Association (NIA-AA) incorporate two staging systems for Aβ pathology, namely the Thal Aβ phase (TAP) and the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) methods. The goal of this study was to compare and contrast results obtained with these two different staging systems for Aβ pathology since this is critical for future correlations of Aβ amyloid imaging data with Aβ neuropathology data based on immunohistochemical detection of...
Source: Acta Neuropathologica - September 25, 2014 Category: Neurology Source Type: research

Aβ seeds resist inactivation by formaldehyde
Abstract Cerebral β-amyloidosis can be exogenously induced by the intracerebral injection of brain extracts containing aggregated β-amyloid (Aβ) into young, pre-depositing Aβ precursor protein- (APP) transgenic mice. Previous work has shown that the induction involves a prion-like seeding mechanism in which the seeding agent is aggregated Aβ itself. Here we report that the β-amyloid-inducing activity of Alzheimer’s disease (AD) brain tissue or aged APP-transgenic mouse brain tissue is preserved, albeit with reduced efficacy, after formaldehyde fixation. Moreover, spectral analy...
Source: Acta Neuropathologica - September 25, 2014 Category: Neurology Source Type: research

FTLD-ALS of TDP-43 type and SCA2 in a family with a full ataxin-2 polyglutamine expansion
We present clinical and pathological features of a family in which a pathological ATXN2 expansion led to frontotemporal lobar degeneration with ALS (FTLD-ALS) in the index case, but typical SCA2 in a son, and compare the neuropathology with a case of typical SCA2. The index case shares the molecular signature of SCA2 with prominent polyglutamine and p62-positive intranuclear neuronal inclusions mainly in the pontine nuclei, while harbouring more pronounced neocortical and spinal TDP-43 pathology. We conclude that ATXN2 mutations can cause not only ALS, but also a neuropathological overlap syndrome of SCA2 and FTLD presenti...
Source: Acta Neuropathologica - September 25, 2014 Category: Neurology Source Type: research

Anti-Aβ antibody target engagement: a response to Siemers et al.
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - September 25, 2014 Category: Neurology Source Type: research

Farewell to oligoastrocytoma: in situ molecular genetics favor classification as either oligodendroglioma or astrocytoma
Abstract Astrocytoma and oligodendroglioma are histologically and genetically well-defined entities. The majority of astrocytomas harbor concurrent TP53 and ATRX mutations, while most oligodendrogliomas carry the 1p/19q co-deletion. Both entities share high frequencies of IDH mutations. In contrast, oligoastrocytomas (OA) appear less clearly defined and, therefore, there is an ongoing debate whether these tumors indeed constitute an entity or whether they represent a mixed bag containing both astrocytomas and oligodendrogliomas. We investigated 43 OA diagnosed in different institutions employing histology, immuno...
Source: Acta Neuropathologica - September 25, 2014 Category: Neurology Source Type: research

Anti-Aβ antibody target engagement: commentary regarding Watt et al. Acta Neuropathol 127:803–810 (2014)
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - September 25, 2014 Category: Neurology Source Type: research

A platelet protein biochip rapidly detects an Alzheimer’s disease-specific phenotype
Abstract Alzheimer’s disease (AD), a multifactorial neurodegenerative condition caused by genetic and environmental factors, is diagnosed using neuropsychological tests and brain imaging; molecular diagnostics are not routinely applied. Studies have identified AD-specific cerebrospinal fluid (CSF) biomarkers but sample collection requires invasive lumbar puncture. To identify AD-modulated proteins in easily accessible blood platelets, which share biochemical signatures with neurons, we compared platelet lysates from 62 AD, 24 amnestic mild cognitive impairment (aMCI), 13 vascular dementia (VaD), and 12 Parki...
Source: Acta Neuropathologica - September 24, 2014 Category: Neurology Source Type: research

A sensitive and specific histopathologic prognostic marker for H3F3A K27M mutant pediatric glioblastomas
Abstract Pediatric glioblastomas (GBM) are highly aggressive and lethal tumors. Recent sequencing studies have shown that ~30 % of pediatric GBM and ~80 % of diffuse intrinsic pontine gliomas show K27M mutations in the H3F3A gene, a variant encoding histone H3.3. H3F3A K27M mutations lead to global reduction in H3K27me3. Our goal was to develop biomarkers for the histopathologic detection of these tumors. Therefore, we evaluated the utility of measuring H3K27me3 global reduction as a histopathologic and prognostic biomarker and tested an antibody directed specifically against the H3.3 K27M mutation in 29...
Source: Acta Neuropathologica - September 9, 2014 Category: Neurology Source Type: research

Specific detection of methionine 27 mutation in histone 3 variants (H3K27M) in fixed tissue from high-grade astrocytomas
Abstract Studies in pediatric high-grade astrocytomas (HGA) by our group and others have uncovered recurrent somatic mutations affecting highly conserved residues in histone 3 (H3) variants. One of these mutations leads to analogous p.Lys27Met (K27M) mutations in both H3.3 and H3.1 variants, is associated with rapid fatal outcome, and occurs specifically in HGA of the midline in children and young adults. This includes diffuse intrinsic pontine gliomas (80 %) and thalamic or spinal HGA (>90 %), which are surgically challenging locations with often limited tumor material available and critical need for...
Source: Acta Neuropathologica - September 9, 2014 Category: Neurology Source Type: research

Aβ immunotherapy for Alzheimer’s disease: effects on apoE and cerebral vasculopathy
Abstract Aβ immunotherapy for Alzheimer’s disease (AD) results in the removal of Aβ plaques and increased cerebral amyloid angiopathy (CAA). In current clinical trials, amyloid-related imaging abnormalities (ARIAs), putatively due to exacerbation of CAA, are concerning side effects. We aimed to assess the role of the Aβ transporter apolipoprotein E (apoE) in the exacerbation of CAA and development of CAA-associated vasculopathy after Aβ immunotherapy. 12 Aβ42-immunized AD (iAD; AN1792, Elan Pharmaceuticals) cases were compared with 28 unimmunized AD (cAD) cases. Immunohistochemistry ...
Source: Acta Neuropathologica - September 7, 2014 Category: Neurology Source Type: research

Erratum to: The role of pro-inflammatory S100A9 in Alzheimer’s disease amyloid-neuroinflammatory cascade
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - September 1, 2014 Category: Neurology Source Type: research

Microglia and monocytes: molecularly defined
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - September 1, 2014 Category: Neurology Source Type: research