Radiotherapy biobanking: current landscape, opportunities, challenges, and future aspirations.

Half of all cancer patients receive radiotherapy, which makes a substantial contribution to their long-term disease control/cure. There are significant inter-patient differences in response, both in terms of efficacy and toxicity (frequently delayed onset) which are difficult to predict. With the introduction of technological improvements (e.

Prospective longitudinal evaluation of cytokines in mild cognitive impairment due to AD and Lewy body disease.

Objectives: We conducted a prospective longitudinal study of plasma cytokines during the Mild Cognitive Impairment (MCI) stage of Lewy body disease and Alzheimer's disease, hypothesizing that cytokine levels would decrease over time and that this would be correlated with decline in cognition.

Methods: Older (≥60) people with MCI were recruited from memory services in healthcare trusts in North East England, UK. MCI was diagnosed as due to Alzheimer's disease (MCI-AD) or Lewy body disease (MCI-LB).

High prevalence of focal and multi-focal somatic genetic variants in the human brain.

Somatic mutations during stem cell division are responsible for several cancers. In principle, a similar process could occur during the intense cell proliferation accompanying human brain development, leading to the accumulation of regionally distributed foci of mutations. Using dual platform >5000-fold depth sequencing of 102 genes in 173 adult human brain samples, we detect and validate somatic mutations in 27 of 54 brains.

Frequency and signature of somatic variants in 1461 human brain exomes.

Purpose: To systematically study somatic variants arising during development in the human brain across a spectrum of neurodegenerative disorders.

Methods: In this study we developed a pipeline to identify somatic variants from exome sequencing data in 1461 diseased and control human brains. Eighty-eight percent of the DNA samples were extracted from the cerebellum.

Somatic variants in autosomal dominant genes are a rare cause of sporadic Alzheimer's disease.

Introduction: A minority of patients with sporadic early-onset Alzheimer's disease (AD) exhibit de novo germ line mutations in the autosomal dominant genes such as APP, PSEN1, or PSEN2. We hypothesized that negatively screened patients may harbor somatic variants in these genes.

Methods: We applied an ultrasensitive approach based on single-molecule molecular inversion probes followed by deep next generation sequencing of 11 genes to 100 brain and 355 blood samples from 445 sporadic patients with AD (>80% exhibited an early onset, <66 years).

Oligogenic genetic variation of neurodegenerative disease genes in 980 postmortem human brains.

Background: Several studies suggest that multiple rare genetic variants in genes causing monogenic forms of neurodegenerative disorders interact synergistically to increase disease risk or reduce the age of onset, but these studies have not been validated in large sporadic case series.

Methods: We analysed 980 neuropathologically characterised human brains with Alzheimer's disease (AD), Parkinson's disease-dementia with Lewy bodies (PD-DLB), frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) and age-matched controls. Genetic variants were assessed using the American College of Medical Genetics criteria for pathogenicity.

Genetic compendium of 1511 human brains available through the UK Medical Research Council Brain Banks Network Resource.

Given the central role of genetic factors in the pathogenesis of common neurodegenerative disorders, it is critical that mechanistic studies in human tissue are interpreted in a genetically enlightened context. To address this, we performed exome sequencing and copy number variant analysis on 1511 frozen human brains with a diagnosis of Alzheimer's disease (AD, n = 289), frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS, n = 252), Creutzfeldt-Jakob disease (CJD, n = 239), Parkinson's disease (PD, n = 39), dementia with Lewy bodies (DLB, n = 58), other neurodegenerative, vascular, or neurogenetic disorders (n = 266), and controls with no significant neuropathology (n = 368). Genomic DNA was extracted from brain tissue in all cases before exome sequencing (Illumina Nextera 62 Mb capture) with variants called by FreeBayes; copy number variant (CNV) analysis (Illumina HumanOmniExpress-12 BeadChip); C9orf72 repeat expansion detection; and APOE genotyping.

Development of passive CLARITY and immunofluorescent labelling of multiple proteins in human cerebellum: understanding mechanisms of neurodegeneration in mitochondrial disease.

CLARITY enables immunofluorescent labelling and imaging of large volumes of tissue to provide a better insight into the three dimensional relationship between cellular morphology and spatial interactions between different cell types. In the current study, we optimise passive CLARITY and immunofluorescent labelling of neurons and mitochondrial proteins in mouse and human brain tissues to gain further insights into mechanisms of neurodegeneration occurring in mitochondrial disease. This is the first study to utilise human cerebellum fixed in paraformaldehyde and cryoprotected in conjunction with formalin-fixed tissues opening up further avenues for use of archived tissue.

Changes to the lateral geniculate nucleus in Alzheimer's disease but not dementia with Lewy bodies.

Aims: Complex visual hallucinations occur in 70% of dementia with Lewy bodies (DLB) cases and significantly affect patient well-being. Visuo-cortical and retinal abnormalities have been recorded in DLB and may play a role in visual hallucinations. The present study aimed to investigate the lateral geniculate nucleus (LGN), a visual relay centre between the retina and visual cortex, to see if changes to this structure underlie visual hallucinations in DLB.

Rapid and equivalent systemic bioavailability of the antidotes HI-6 and dicobalt edetate via the intraosseous and intravenous routes.

Background: Rapid and effective administration of antidotes by emergency medical responders is needed to improve the survival of patients severely poisoned after deliberate release of chemical weapons, but intravenous access is difficult to obtain while wearing personal protective equipment and in casualties with circulatory collapse. To test the hypothesis that rapid and substantial bioavailability of the antidotes HI-6 oxime and dicobalt edetate can be achieved via the intraosseous (IO) route, plasma concentration-time profiles of these antidotes were compared after administration by the intravenous and IO routes in a minipig animal model.

Methods: 12 male Göttingen minipigs were randomly allocated to receive 7.

Transferrin and HFE genes interact in Alzheimer's disease risk: the Epistasis Project.

Iron overload may contribute to the risk of Alzheimer's disease (AD). In the Epistasis Project, with 1757 cases of AD and 6295 controls, we studied 4 variants in 2 genes of iron metabolism: hemochromatosis (HFE) C282Y and H63D, and transferrin (TF) C2 and -2G/A. We replicated the reported interaction between HFE 282Y and TF C2 in the risk of AD: synergy factor, 1.

Common genetic variation within the low-density lipoprotein receptor-related protein 6 and late-onset Alzheimer's disease.

Genome-wide linkage studies have defined a broad susceptibility region for late-onset Alzheimer's disease on chromosome 12, which contains the Low-Density Lipoprotein Receptor-Related Protein 6 (LRP6) gene, a coreceptor for Wnt signaling. Here, we report the association between common LRP6 variants and late-onset Alzheimer's disease in a multicenter case-control series as well as in a large family-based series ascertained by the National Institute of Mental Health-National Institute on Aging Genetics Initiative. As shown in the genome-wide linkage studies, our association depends mainly on apolipoprotein E-epsilon4 (APOE-epsilon4) carrier status.

The MAPT H1c risk haplotype is associated with increased expression of tau and especially of 4 repeat containing transcripts.

Previously we have shown that the H1c haplotype on the background of the H1 clade of haplotypes at the MAPT locus is associated with increased risk for progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and Alzheimer's disease (AD). Here we replicated the association with AD in an additional autopsy confirmed series. We show that this haplotype increases both the expression of total MAPT transcript as well as specifically increasing the proportion of 4 microtubule binding repeat containing transcripts.

Preliminary observation of elevated levels of nanocrystalline iron oxide in the basal ganglia of neuroferritinopathy patients.

Magnetometry analysis of brain tissue sub-samples from two neuroferritinopathy patients provides a preliminary indication that the amount of magnetic iron compounds associated with this rare disease is significantly larger than in age/sex-matched controls. The primary iron compounds contributing to the remnant magnetization of the tissue above 50 K and at body temperature are both blocked and superparamagnetic (SPM) biogenic magnetite (Fe3O4) and/or maghemite (gamma-Fe2O3). The concentration of SPM magnetite is significant and appears to be proportional to the concentration of ferritin, which varies with progression of the disease.

Genetic variability in CHMP2B and frontotemporal dementia.

A nonsense/protein chain-terminating mutation in the CHMP2B gene has recently been reported as a cause of frontotemporal dementia (FTD) in the single large family known to show linkage to chromosome 3. Screening for mutations in this gene in a large series of FTD families and individual patients led to the identification of a protein-truncating mutation in 2 unaffected members of an Afrikaner family with FTD, but not in their affected relatives. The putative pathogenicity of CHMP2B mutations for dementia is discussed.

A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease.

Strong evidence of linkage to late-onset Alzheimer disease (LOAD) has been observed on chromosome 10, which implicates a wide region and at least one disease-susceptibility locus. Although significant associations with several biological candidate genes on chromosome 10 have been reported, these findings have not been consistently replicated, and they remain controversial. We performed a chromosome 10-specific association study with 1,412 gene-based single-nucleotide polymorphisms (SNPs), to identify susceptibility genes for developing LOAD.

Ubiquilin 1 polymorphisms are not associated with late-onset Alzheimer's disease.

Several studies have reported evidence for linkage of late-onset Alzheimer's disease (LOAD) to chromosome 9. Recently, an intronic polymorphism affecting alternative splicing of exon 8 of ubiquilin 1 (UBQLN1) was reported to be associated with LOAD. We attempted to replicate this observation by genotyping this polymorphism, rs12344615 (also known as UBQ-8i), in a large sample of 1,544 LOAD cases and 1,642 nondemented controls.

APOA1 polymorphism influences risk for early-onset nonfamiliar AD.

Alterations in cholesterol homeostasis influence the risk for Alzheimer's disease (AD). Apolipoprotein A1 is the major apolipoprotein of the high-density lipoprotein and is involved in reverse cholesterol transport. Variation in the apolipoprotein A1 gene (APOA1) might influence the function of the protein, and thus brain cholesterol metabolism, leading to an increased risk for AD.

Association studies between risk for late-onset Alzheimer's disease and variants in insulin degrading enzyme.

Linkage studies have suggested there is a susceptibility gene for late onset Alzheimer's disease (LOAD) in a broad region of chromosome 10. A strong positional and biological candidate is the gene encoding the insulin-degrading enzyme (IDE), a protease involved in the catabolism of Abeta. However, previous association studies have produced inconsistent results.

Dementia with Lewy bodies.

The objective was to summarize recent findings about the clinical features, diagnosis and investigation of dementia with Lewy (DLB) bodies, together with its neuropathology, neurochemistry and genetics. Dementia with Lewy bodies (DLB) is a primary, neurodegenerative dementia sharing clinical and pathological characteristics with both Parkinson's disease (PD) and Alzheimer's disease (AD). Antiubiquitin immunocytochemical staining, developed in the early 1990s, allowed the frequency and distribution of cortical LBs to be defined.