Chemical imaging analysis of the brain with X-ray methods

Cells employ various metal and metalloid ions to augment the structure and the function of proteins and to assist with vital biological processes. In the brain they mediate biochemical processes, and disrupted metabolism of metals may be a contributing factor in neurodegenerative disorders. In this tutorial review we will discuss the particular role of X-ray methods for elemental imaging analysis of accumulated metal species and metal-containing compounds in biological materials, in the context of post-mortem brain tissue. X-rays have the advantage that they have a short wavelength and can penetrate through a thick biological sample. Many of the X-ray microscopy techniques that provide the greatest sensitivity and specificity for trace metal concentrations in biological materials are emerging at synchrotron X-ray facilities. Here, the extremely high flux available across a wide range of soft and hard X-rays, combined with state-of-the-art focusing techniques and ultra-sensitive detectors, makes it viable to undertake direct imaging of a number of elements in brain tissue. The different methods for synchrotron imaging of metals in brain tissues at regional, cellular, and sub-cellular spatial resolution are discussed. Methods covered include X-ray fluorescence for elemental imaging, X-ray absorption spectrometry for speciation imaging, X-ray diffraction for structural imaging, phase contrast for enhanced contrast imaging and scanning transmission X-ray microscopy for spectromicroscopy. Two- and three-dimensional (confocal and tomographic) imaging methods are considered as well as the correlation of X-ray microscopy with other imaging tools

Iron deficiency in parkinsonism : region-specific iron dysregulation in Parkinson's disease and multiple system atrophy

Alpha synuclein pathology is widespread and found in diverse cell types in multiple system atrophy (MSA) as compared to Parkinson's disease (PD). The reason for this differential distribution is unknown. Regional differences in the distribution of iron are associated with neurodegenerative diseases, and here we characterize the relationship between iron homeostasis proteins and regional concentration, distribution and form of iron in MSA and PD. In PD substantia nigra, tissue iron and expression of the iron export protein ferroportin increased, while the iron storage protein ferritin expression was unchanged. In the basis pontis of MSA cases, increased total iron concentration coupled with a disproportionate increase in ferritin in dysmorphic microglia and a reduction in ferroportin expression. This is supported by isothermal remanent magnetisation evidence consistent with elevated concentrations of ferritin-bound iron in MSA basis pontis. Conventional opinion holds that excess iron is involved in neurodegeneration. Our data support that this may be the case in PD. While region-specific changes in iron are evident in both PD and MSA, the mechanisms of iron dysregulation appear quite distinct, with a failure to export iron from the MSA basis pontis coupling with significant intracellular accumulation of ferritin iron. This pattern also occurs, to a lesser extent, in the MSA putamen. Despite the excess tissue iron, the manner of iron dysregulation in MSA is reminiscent of changes in anemia of chronic disease, and our preliminary data, coupled with the widespread pathology and involvement of multiple cell types, may evidence a deficit in bioavailabile iron

A New Ant Species of the Genus Tetramorium Mayr, 1855 (Hymenoptera: Formicidae) from Saudi Arabia, with a Revised Key to the Arabian Species

Tetramorium amalae sp. n. is described and illustrated from Saudi Arabia based on two worker caste specimens collected in Al Bahah region. The new species belongs to the T. shilohense group and appears to be closely related to T. dysderke Bolton from Nigeria. T. amalae is distinguished by having well-developed frontal carinae, smaller eyes, greater head length and width, greater pronotal width, and the petiole node is longer than broad. Tetramorium latinode Collingwood & Agosti is recorded for the first time from Saudi Arabia and for only the second time since the original description. The worker caste of T. latinode is redescribed and illustrated using scanning electron micrographs to facilitate recognition and the gyne is described for the first time with observations given on species relationships, biology and habitat. A revised key to the nineteen Tetramorium species recorded from Arabian Peninsula based on worker castes is provided. Tetramorium bicarinatum (Nylander) is recorded for the first time from Saudi Arabia. It is suggested that T. amalae and T. latinode are endemic to the Arabian Peninsula

Analysing the impact of iron dysmetabolism on regional metal ion distribution in the brain

An Iron Overload and an H-Ferritin Deficient Mouse Model were used to examine the impact of disrupted iron metabolism on the brain. Brain sections were imaged and compared using Synchrotron μXRF spectroscopy. Quantitative measurement of the relative metal ion concentrations for iron, copper and zinc were made across selected regions of interest in the brain. It was generally found that metal ion concentrations of iron and zinc decreased in specific regions in the Iron Overload condition compared with the control, with copper increasing in only one region. Few regions differed in metal ion concentration between the H-Ferritin Deficient Model and the control. The three conditions exhibited similar / identical results for metal ion concentrations in many brain regions, indicating the validity of the method used for comparison between samples. It is clear that there exists a complex relationship between these trace metal

Effective R2 relaxation rate, derived from dual-contrast fast-spin-echo MRI, enables detection of hemisphere differences in iron level and dopamine function in Parkinson’s disease and healthy individuals

Background: Clinical estimates of brain iron concentration are achievable with quantitative transverse relaxation rate R2, via time-consuming multiple spin-echo (SE) sequences. The objective of this study was to investigate whether quantitative iron-sensitive information may be derived from 3.0 T dual-contrast fast-spin-echo (FSE) sequences (typically employed in anatomical non-quantitative evaluations), as a routinely-collected alternative to evaluate iron levels in healthy (HC) and Parkinson’s disease (PD) brains. New method: MRI 3.0 T FSE data from the Parkinson’s Progression Markers Initiative (PPMI) (12 PD, 12 age- and gender-matched HC subjects) were cross-sectionally and longitudinally evaluated. A new measure, ‘effective R2’, was calculated for bilateral subcortical grey matter (caudate nucleus, putamen, globus pallidus, red nucleus, substantia nigra). Linear regression analysis was performed to correlate ‘effective R2’ with models of age-dependent brain iron concentration and striatal dopamine transporter (DaT) receptor binding ratio. Results: Effective R2 was strongly correlated with estimated brain iron concentration. In PD, putaminal effective R2 difference was observed between the hemispheres contra-/ipsi-lateral to the predominantly symptomatic side at onset. This hemispheric difference was correlated with the putaminal DaT binding ratios in PD. Comparison with existing method(s): Effective R2, derived from rapid dual-contrast FSE sequences, showed viability as an alternative to R2 from SE sequences. Linear correlation of effective R2 with estimated iron concentration was comparable to documented iron-dependent R2. The effective R2 correlation coefficient was consistent with theoretical R2 iron-dependence at 3.0 T. Conclusions: Effective R2 has clinical potential as a fast quantitative method, as an alternative to R2, to aid evaluation of brain iron levels and DaT function

People with aphasia creating an aphasia friendly website: The DMU4 experience

People with aphasia creating an aphasia friendly website: The DMU4 experience Bixley,M., DMU4, Hall, R., Weale, R., Collingwood, J., Marshall, F. & Hamilton, C. Background Information The DMU4 Conversation group is part of Aphasia Leicester; a community based, voluntary sector, long term support organisation for People with Aphasia (PWA). Members of DMU4 have experienced being unable to access information about their condition because of the way in which the information is presented. These personal experiences are supported by research such as the Care Quality Commission’s (2011) report that suggested that only 40% of social services in Britain provided information in an accessible way for PWA post stroke. In 2011, DMU4 created a leaflet about aphasia that was designed to be used in acute hospitals to educate stroke survivors, relatives and hospital staff about aphasia (Bixley et al, 2011). This leaflet has been distributed to hospitals, surgeries and Speech and Language Therapy Departments in Leicestershire and Rutland. Last year DMU4 decided that they would like to embark on a new project; creating a website about aphasia that was also accessible to PWA. Method The group decided that there were three main factors that needed to guide the construction and structure of the website. Firstly, people with aphasia would appear on the website as aphasia experts. Secondly, navigation around the website should be aphasia friendly, based on visual images and accessible written language. Lastly, members of DMU4 would retain copyright over their own images. For this reason, the site was hosted on “Our DMU Commons” a self organising space that allows users to co construct their own website using open source software. The content of the website was agreed through group discussions. Following these discussions, nine DMU4 members attended a whole day filming session in which their perceptions of aphasia were recorded. Films were then transcribed and edited into eleven themes using a grounded approach. Skeat & Perry (2007) suggest this approach is useful when investigating information that is not available anywhere else, such as the information presented in this website. Informed consent was elicited through discussions, meetings, film and website screenings and signed agreement. Results and discussion The DMU4 website project has two tangible outcomes. The first is that the site will be available to people who want to learn about aphasia. The second is that the resource will be available for Speech and Language Therapy students. Learning activities will enable students to practise recognising and understand aphasia from the perspective of those who live with the loss of language post stroke. The practices of DMU4 are rooted firmly in the social approach to aphasia therapy (Pound, Parr, Lindsay and Woolf, 2000). It is hoped that the website’s third, less measurable, outcome will be a contribution to overcoming the attitudinal and informational barriers that are experienced by PWA post stoke. References BIXLEY, M., DMU4 & HAMILTON, C. (2011) Aphasia – an information leaflet designed by people with aphasia. British Aphasiology Society Biennial International Conference Book of Abstracts, 12. CARE QUALITY COMMISSION (2011) Supporting life after stroke: A review of services for people who have had a stroke and their carers. London: Care Quality Commission. SKEAT, J. & PERRY, A. (2008). Grounded theory as a method for research in speech and language therapy. International Journal of Language and Communication Disorders, 43, 2, 95-109. POUND, C., PARR, S., LINDSAY, J. & WOOLF, C. (2000) Beyond Aphasia: Therapies for Living with Communication Disability. Bicester: Winslow

Iron stored in ferritin is chemically reduced in the presence of aggregating Aβ(1-42).

Atypical low-oxidation-state iron phases in Alzheimer's disease (AD) pathology are implicated in disease pathogenesis, as they may promote elevated redox activity and convey toxicity. However, the origin of low-oxidation-state iron and the pathways responsible for its formation and evolution remain unresolved. Here we investigate the interaction of the AD peptide β-amyloid (Aβ) with the iron storage protein ferritin, to establish whether interactions between these two species are a potential source of low-oxidation-state iron in AD. Using X-ray spectromicroscopy and electron microscopy we found that the co-aggregation of Aβ and ferritin resulted in the conversion of ferritin's inert ferric core into more reactive low-oxidation-states. Such findings strongly implicate Aβ in the altered iron handling and increased oxidative stress observed in AD pathogenesis. These amyloid-associated iron phases have biomarker potential to assist with disease diagnosis and staging, and may act as targets for therapies designed to lower oxidative stress in AD tissue

Analysis of neuronal iron deposits in Parkinson's disease brain tissue by synchrotron x-ray spectromicroscopy

Neuromelanin-pigmented neurons, which are highly susceptible to neurodegeneration in the Parkinson’s disease substantia nigra, harbour elevated iron levels in the diseased state. Whilst it is widely believed that neuronal iron is stored in an inert, ferric form, perturbations to normal metal homeostasis could potentially generate more reactive forms of iron capable of stimulating toxicity and cell death. However, non-disruptive analysis of brain metals is inherently challenging, since use of stains or chemical fixatives, for example, can significantly influence metal ion distributions and/or concentrations in tissues

N=2 Generalized Superconformal Quiver Gauge Theory

Four dimensional N=2 generalized superconformal field theory can be defined by compactifying six dimensional (0,2) theory on a Riemann surface with regular punctures. In previous studies, gauge coupling constant space is identified with the moduli space of punctured Riemann surface M_{g,n}. We show that the weakly coupled gauge group description corresponds to a stable nodal curve, and the coupling space is actually the Deligne-Mumford compactification \bar{M}_{g,n}. We also give an algorithm to determine the weakly coupled gauge group and matter content in any duality frame.Comment: v2, reorganizing the materials, discussions on 2d CFT is remove