Pathways and patterns of cell loss in verified Alzheimer's disease: a factor and cluster analysis of clinico-pathological subgroups

Thirty-seven patients with neuropathologicaUy verified Alzheimer's disease (AD) have been studied prospectively. A principal components analysis of neuron numbers in cortical and subcortical areas revealed two variables: Variable I with high loadings for the hippocampo-parahippocampo-parietal neuron counts and Variable n with high loadings for coeruleo-frontal cell numbers. Both may reflect functional neuroanatomical connections which may act as pathways of neurodegeneration in AD. A cluster analysis based on these neuron numbers yielded three groups of patients: Cluster A with low hippocampoparahippocampo-parietal cell counts, Cluster B with well-preserved neuron numbers, and Cluster C with low coeruleo-frontal neuron numbers. Differences in clinical features between these patient groups indicated the potential clinical relevance of these clusters

Surgical trial in traumatic intracerebral haemorrhage (STITCH) : A randomised controlled trial of early surgery compared with Initial conservative treatment

Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme.Peer reviewedPublisher PD

New Antibody-Free Mass Spectrometry-Based Quantification Reveals That C9ORF72 Long Protein Isoform Is Reduced in the Frontal Cortex of Hexanucleotide-Repeat Expansion Carriers

Frontotemporal dementia (FTD) is a fatal neurodegenerative disease characterized by behavioral and language disorders. The main genetic cause of FTD is an intronic hexanucleotide repeat expansion (G4C2)n in the C9ORF72 gene. A loss of function of the C9ORF72 protein associated with the allele-specific reduction of C9ORF72 expression is postulated to contribute to the disease pathogenesis. To better understand the contribution of the loss of function to the disease mechanism, we need to determine precisely the level of reduction in C9ORF72 long and short isoforms in brain tissue from patients with C9ORF72 mutations. In this study, we developed a sensitive and robust mass spectrometry (MS) method for quantifying C9ORF72 isoform levels in human brain tissue without requiring antibody or affinity reagent. An optimized workflow based on surfactant-aided protein extraction and pellet digestion was established for optimal recovery of the two isoforms in brain samples. Signature peptides, common or specific to the isoforms, were targeted in brain extracts by multiplex MS through the parallel reaction monitoring mode on a Quadrupole–Orbitrap high resolution mass spectrometer. The assay was successfully validated and subsequently applied to frontal cortex brain samples from a cohort of FTD patients with C9ORF72 mutations and neurologically normal controls without mutations. We showed that the C9ORF72 short isoform in the frontal cortices is below detection threshold in all tested individuals and the C9ORF72 long isoform is significantly decreased in C9ORF72 mutation carriers

Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity.

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once

Chromatin Conformation Links Putative Enhancers in Intracranial Aneurysm–Associated Regions to Potential Candidate Genes

Background: We previously showed that intracranial aneurysm (IA)–associated single-nucleotide polymorphisms are enriched in promoters and putative enhancers identified in the human circle of Willis, on which IAs develop, suggesting a role for promoters and enhancers in IAs. We further investigated the role of putative enhancers in the pathogenesis of IA by identifying their potential target genes and validating their regulatory activity. Methods and Results: Using our previously published circle of Willis chromatin immunoprecipitation and sequencing data, we selected 34 putative enhancers in IA-associated regions from genome-wide association studies. We then used a chromatin conformation capture technique to prioritize target genes and found that 15 putative enhancers interact with the promoters of 6 target genes: SOX17, CDKN2B, MTAP, CNNM2, RPEL1, and GATA6. Subsequently, we assessed the activity of these putative enhancers in vivo in zebrafish embryos and confirmed activity for 8 putative enhancers. Last, we found that all 6 target genes are expressed in the circle of Willis, on the basis of RNA sequencing data and in situ hybridization. Furthermore, in situ hybridization showed that these genes are expressed in multiple cell types in the circle of Willis. Conclusions: In 4 of 6 IA-associated genome-wide association study regions, we identified 8 putative enhancers that are active in vivo and interact with 6 nearby genes, suggesting that these genes are regulated by the identified putative enhancers. These genes, SOX17, CDKN2B, MTAP, CNNM2, RPEL1, and GATA6, are therefore potential candidate genes involved in IA pathogenesis and should be studied using animal models in the future

Levels of Retinal Amyloid-β Correlate with Levels of Retinal IAPP and Hippocampal Amyloid-β in Neuropathologically Evaluated Individuals

BACKGROUND: Previous studies have used immunohistology to demonstrate Alzheimer's disease (AD) characteristic accumulation of amyloid-β (Aβ) in the retina of AD patients, a finding indicating retina examination as a potential diagnostic tool for AD pathology. OBJECTIVE: To further explore this idea by investigating whether levels of Aβ42 and Aβ40 in retina are associated with corresponding levels in hippocampus, neuropathological assessments, apolipoprotein E (APOE) genotype, and levels of islet amyloid polypeptide (IAPP). METHODS: Levels of high molecular weight (HMW) Aβ42, Aβ40, and IAPP in ultra-centrifuged homogenates of retina and hippocampus from patients with AD, multiple sclerosis, AD with Lewy bodies, and non-demented controls were analyzed using Mesoscale Discovery electrochemiluminescence technology employing immunoassay and enzyme-linked immunosorbent assay. RESULTS: Higher levels of retinal and hippocampal Aβ42-HMW, Aβ40-HMW, and IAPP-HMW were found in individuals with high neuropathological scores of Aβ plaques and in individuals carrying the APOEɛ4 allele. The retinal levels of Aβ42-HMW and Aβ40-HMW correlated with corresponding levels in hippocampus as well as with neurofibrillary tangles (NFT) and Aβ scores. Retinal IAPP-HMW correlated with retinal levels of Aβ42-HMW and with NFT and Aβ scores. CONCLUSION: These results show that different isoforms of Aβ can be detected in the human retina and moreover support the growing number of studies indicating that AD-related pathological changes occurring in the brain could be reflected in the retina

Microglia in post-mortem brain tissue of patients with bipolar disorder are not immune activated

Genetic, epidemiological, and biomarker studies suggest that the immune system is involved in the pathogenesis of bipolar disorder (BD). It has therefore been hypothesized that immune activation of microglia, the resident immune cells of the brain, is associated with the disease. Only a few studies have addressed the involvement of microglia in BD so far and a more detailed immune profiling of microglial activation is lacking. Here, we applied a multi-level approach to determine the activation state of microglia in BD post-mortem brain tissue. We did not find differences in microglial density, and mRNA expression of microglial markers in the medial frontal gyrus (MFG) of patients with BD. Furthermore, we performed in-depth characterization of human primary microglia isolated from fresh brain tissue of the MFG, superior temporal gyrus (STG), and thalamus (THA). Similarly, these ex vivo isolated microglia did not show elevated expression of inflammatory markers. Finally, challenging the isolated microglia with LPS did not result in an increased immune response in patients with BD compared to controls. In conclusion, our study shows that microglia in post-mortem brain tissue of patients with BD are not immune activated

Levels of retinal IAPP are altered in Alzheimer's disease patients and correlate with vascular changes and hippocampal IAPP levels

Islet amyloid polypeptide (IAPP) forms toxic aggregates in the brain of patients with Alzheimer's disease (AD). Whether IAPP also affects the retina in these patients is still unknown. Levels of IAPP in soluble and insoluble homogenate fractions of retina and hippocampus from AD patients and nondemented controls were analyzed using ELISA. Number of pericytes and vessel length were determined by analysis of immunostained retina and hippocampus. Insoluble retinal fractions of AD patients contained lower levels of unmodified IAPP, whereas soluble retinal fractions contained increased levels of the same. Total IAPP levels and pericyte numbers in retina mirrored corresponding variables in the hippocampus. Moreover, levels of total unmodified IAPP correlated negatively with the vessel length both in retina and hippocampus across the group and positively with pericyte numbers in retina in AD patients. Our studies indicate that changes in brain IAPP are reflected by corresponding levels in the retina. Our results also suggest modification of IAPP as an important event implicated in vascular changes associated with AD