Chris Fowler

Plasma Amyloid-β as a Biomarker in Alzheimer's Disease: The AIBL Study of Aging

Amyloid-beta (Abeta) plays a central role in the pathogenesis of Alzheimers disease (AD) and has been postulated as a potential biomarker for AD. However, there is a lack of consensus as to its suitability as an AD biomarker. The objective of this study was to determine the significance of plasma Abeta as an AD biomarker and its relationship with Abeta load and to determine the effect of different assay methods on the interpretation of Abeta levels. Plasma Abeta1-40, Abeta1-42, and N-terminal cleaved fragments were measured using both a commercial multiplex assay and a well-documented ELISA in 1032 individuals drawn from the well-characterized Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. Further, Abeta levels were compared to Abeta load derived from positron-emission tomography (PET) with the Pittsburgh compound B (PiB). Lower Abeta1-42 and Abeta1-42/1-40 ratio were observed in patients with AD and inversely correlated with PiB-PET derived Abeta load. However, assay methodology significantly impacted the interpretation of data. The cross-sectional analysis of plasma Abeta isoforms suggests that they may not be sufficient per se to diagnose AD. The value of their measurement in prognosis and monitoring of AD interventions needs further study, in addition to future longitudinal comparisons together with other predictors, which will determine whether plasma Abeta has diagnostic value in a panel of biomarkers.

Prognostic serum miRNA biomarkers associated with Alzheimer's disease shows concordance with neuropsychological and neuroimaging assessment

There is no consensus for a blood-based test for the early diagnosis of Alzheimer’s disease (AD). Expression profiling of small non-coding RNA’s, microRNA (miRNA), has revealed diagnostic potential in human diseases. Circulating miRNA are found in small vesicles known as exosomes within biological fluids such as human serum. The aim of this work was to determine a set of differential exosomal miRNA biomarkers between healthy and AD patients, which may aid in diagnosis. Using next-generation deep sequencing, we profiled exosomal miRNA from serum (N=49) collected from the Australian Imaging, Biomarkers and Lifestyle Flagship Study (AIBL). Sequencing results were validated using quantitative reverse transcription PCR (qRT-PCR; N=60), with predictions performed using the Random Forest method. Additional risk factors collected during the 4.5-year AIBL Study including clinical, medical and cognitive assessments, and amyloid neuroimaging with positron emission tomography were assessed. An AD-specific 16-miRNA signature was selected and adding established risk factors including age, sex and apolipoprotein ɛ4 (APOE ɛ4) allele status to the panel of deregulated miRNA resulted in a sensitivity and specificity of 87% and 77%, respectively, for predicting AD. Furthermore, amyloid neuroimaging information for those healthy control subjects incorrectly classified with AD-suggested progression in these participants towards AD. These data suggest that an exosomal miRNA signature may have potential to be developed as a suitable peripheral screening tool for AD.

High performance plasma amyloid-β biomarkers for Alzheimer’s disease

To facilitate clinical trials of disease-modifying therapies for Alzheimer’s disease, which are expected to be most efficacious at the earliest and mildest stages of the disease, supportive biomarker information is necessary. The only validated methods for identifying amyloid-β deposition in the brain—the earliest pathological signature of Alzheimer’s disease—are amyloid-β positron-emission tomography (PET) imaging or measurement of amyloid-β in cerebrospinal fluid. Therefore, a minimally invasive, cost-effective blood-based biomarker is desirable. Despite much effort, to our knowledge, no study has validated the clinical utility of blood-based amyloid-β markers. Here we demonstrate the measurement of high-performance plasma amyloid-β biomarkers by immunoprecipitation coupled with mass spectrometry. The ability of amyloid-β precursor protein (APP)669–711/amyloid-β (Aβ)1–42 and Aβ1–40/Aβ1–42 ratios, and their composites, to predict individual brain amyloid-β-positive or -negative status was determined by amyloid-β-PET imaging and tested using two independent data sets: a discovery data set (Japan, n = 121) and a validation data set (Australia, n = 252 including 111 individuals diagnosed using 11C-labelled Pittsburgh compound-B (PIB)-PET and 141 using other ligands). Both data sets included cognitively normal individuals, individuals with mild cognitive impairment and individuals with Alzheimer’s disease. All test biomarkers showed high performance when predicting brain amyloid-β burden. In particular, the composite biomarker showed very high areas under the receiver operating characteristic curves (AUCs) in both data sets (discovery, 96.7%, n = 121 and validation, 94.1%, n = 111) with an accuracy approximately equal to 90% when using PIB-PET as a standard of truth. Furthermore, test biomarkers were correlated with amyloid-β-PET burden and levels of Aβ1–42 in cerebrospinal fluid. These results demonstrate the potential clinical utility of plasma biomarkers in predicting brain amyloid-β burden at an individual level. These plasma biomarkers also have cost–benefit and scalability advantages over current techniques, potentially enabling broader clinical access and efficient population screening.

Personhood and Social Relations in the British Neolithic with a Study from the Isle of Man

Studies of collective or corporate burial in the British Neolithic have focused largely on ancestors, clans and lineages, or the production of a microcosm of reality. Social relations are often described as egalitarian, or egalitarianism is taken to be the ideological impetus for corporate burial, belying inequalities in life. Studies of individual burial focus more on concepts of individual power, autonomous agency, status and possession. In this contribution acts of depositing Neolithic bones are interpreted as citations of social relations. The possibilities for studying Neolithic social relations between different aspects of life (human, animal, object, place) are explored using theories developed to understand how persons - and their worlds - are produced through activity. Such activities are considered as struggles with different kinds of ideological regulatory fictions about personal identity and social relations. The study starts with a consideration of ethnographic approaches to personhood, reviews recent work on British Neolithic mortuary practices, and concludes with a case study from the Isle of Man.

The emergent past : a relational realist archaeology of early bronze age mortuary practices

ACKNOWLEDGEMENTS LIST OF ILLUSTRATIONS 1. Introduction 2. Relational realism and the nature of archaeological evidence 3. Theories as actants: translating mortuary practice 4. Packing and unpacking black boxes: pattern and diversity in Chalcolithic and Early Bronze Age mortuary practices from Northeast England 5. Changing places, changing communities 6. Themes emerging from Chalcolithic and Early Bronze Age mortuary practices in Northeast England 7. The emergent past circulation, articulation, and entanglement APPENDIX A Key details of sites in the dataset APPENDIX B Key details of mortuary deposits in the dataset BIBLIOGRAPHY INDEX

Enduring relations: Exploring a paradox of new materialism

In this article, the authors examine tensions between understandings of material things as either bundles of relations or as things-in-themselves. Rather than take either of these positions, they instead set out an argument for approaches that allow them to modulate between these understandings whilst treating both as relational. Taking such a position allows them to consider how things endure through time without returning to any notion of essence. They explore the theoretical arguments through an analysis of one particular enduring material phenomenon: the Neolithic chambered tomb of West Kennet.

Relational Personhood Revisited

This article revisits one of the key heuristic devices archaeologists have used to appreciate personhood over the last 15 years—the idea that there is a tension between individual and dividual aspects of personhood. I argue that personhood is always relational, but in varied ways, and propose a revised heuristic approach to assist with appreciating diversity in the multi-dimensional and multi-modal character of personhood.

Relational typologies, assemblage theory and Early Bronze Age burials.

This article argues that artefact types and typologies are kinds of assemblages, presenting an explicitly relational interpretation of typology grounded in a more-than-representational assemblage theory. In the process it evaluates recent approaches to typology, and the interpretations these typologies have supported, and compares these with approaches which emphasize materiality and experience. It then illustrates the benefit of drawing these two angles of analysis closer together within an approach grounded in a more-than-representational assemblage theory. Throughout, the discussion revolves around British Chalcolithic and Early Bronze Age burials and types of artefacts commonly found within them. The core argument is that, if used appropriately, typologies are not constraints to the appreciation of distinctiveness, difference and relationality in the past, but can rather form an important tool in detecting those relations and making sense of different past ways of becoming.

Rates of (Ex)change

This contribution investigates how specific tempos of activity remind people of their place in the material world. It focuses in particular on the relationship between personhood, change, the dead, and processes of decay and regrowth. It is suggested that human bodies and the bodies of artefacts and places were all repeatedly transformed in complimentary ways during the earlier Neolithic of southern Britain. Incremental and gradual changes applied to each type of body. The repeated transformation of those bodies reminded the living of their place in the material world, their connections with the dead and with other bodies including the bodies of monumental places. These transformative acts both commemorated expected features of social identities and also formed the arena through which those identities could themselves be revised.

PLASMA BIOMARKER WITH HIGH ACCURACY IN PREDICTING BRAIN AMYLOID-β BURDEN: INITIAL RESULTS ACROSS TWO INDEPENDENT LARGE COHORTS—NCGG (JAPAN) AND AIBL (AUSTRALIA)

dementia, delirium with dementia or delirium alone. Methods: A systematic review and meta-analysis was undertaken using a predefined search strategy. Titles and abstracts of studies were screened to identify those meeting criteria for inclusion. The data was then extracted and coded according to preselected characteristics. The findings from all included studies were synthetized into a standardised extraction form.Meta-analysis was undertaken by calculating the weighted mean difference (WMD) between blood levels patients with dementia, delirium with dementia or delirium alone. Results:An 18-kDa translocator protein (TSPO) has been identified which is expressed on activated microglia, activated astrocytes and macrophages. This biomarker has been used to quantify neuroinflamation and has demonstrated an ability to differentiate mild cognitive impairment (MCI) from Alzheimer’s dementia (AD). YKL-40, a biomarker expressed on astrocytes in the CSF also appears useful as it increase prevalence is associated with other markers of neurodegeneration such as tau and phosphorylated tau (p-tau). Levels of this biomarker are inversely associated with cortical thickness in the temporal regions of the brain. Unfortunately levels of TSPO and YKL-40 have not proven useful when sampled from the plasma. Conclusions:The identification neuroinflammatory biomarkers that can be used both diagnostically and prognostically is clinically useful. However further work is needed to find and develop reliable biomarkers that can be used to differentiate between dementia, delirium with dementia or delirium alone. It is also necessary to develop biomarkers that can make use of serum samples rather than needing CSF due to the discomfort and difficulty in obtaining the latter.