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4 Evaluating Plasma GFAP for the Detection of Alzheimer’s Disease Dementia
- Madeline Ally, Henrik Zetterberg, Kaj Blennow, Nicholas J. Ashton, Thomas K. Karikari, Hugo Aparicio, Michael A. Sugarman, Brandon Frank, Yorghos Tripodis, Ann C. McKee, Thor D. Stein, Brett Martin, Joseph N. Palmisano, Eric G. Steinberg, Irene Simkina, Lindsay Farrer, Gyungah Jun, Katherine W. Turk, Andrew E. Budson, Maureen K. O’Connor, Rhoda Au, Wei Qiao Qiu, Lee E. Goldstein, Ronald Killiany, Neil W. Kowall, Robert A. Stern, Jesse Mez, Michael L. Alosco
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 408-409
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Objective:
Blood-based biomarkers represent a scalable and accessible approach for the detection and monitoring of Alzheimer’s disease (AD). Plasma phosphorylated tau (p-tau) and neurofilament light (NfL) are validated biomarkers for the detection of tau and neurodegenerative brain changes in AD, respectively. There is now emphasis to expand beyond these markers to detect and provide insight into the pathophysiological processes of AD. To this end, a reactive astrocytic marker, namely plasma glial fibrillary acidic protein (GFAP), has been of interest. Yet, little is known about the relationship between plasma GFAP and AD. Here, we examined the association between plasma GFAP, diagnostic status, and neuropsychological test performance. Diagnostic accuracy of plasma GFAP was compared with plasma measures of p-tau181 and NfL.
Participants and Methods:This sample included 567 participants from the Boston University (BU) Alzheimer’s Disease Research Center (ADRC) Longitudinal Clinical Core Registry, including individuals with normal cognition (n=234), mild cognitive impairment (MCI) (n=180), and AD dementia (n=153). The sample included all participants who had a blood draw. Participants completed a comprehensive neuropsychological battery (sample sizes across tests varied due to missingness). Diagnoses were adjudicated during multidisciplinary diagnostic consensus conferences. Plasma samples were analyzed using the Simoa platform. Binary logistic regression analyses tested the association between GFAP levels and diagnostic status (i.e., cognitively impaired due to AD versus unimpaired), controlling for age, sex, race, education, and APOE e4 status. Area under the curve (AUC) statistics from receiver operating characteristics (ROC) using predicted probabilities from binary logistic regression examined the ability of plasma GFAP to discriminate diagnostic groups compared with plasma p-tau181 and NfL. Linear regression models tested the association between plasma GFAP and neuropsychological test performance, accounting for the above covariates.
Results:The mean (SD) age of the sample was 74.34 (7.54), 319 (56.3%) were female, 75 (13.2%) were Black, and 223 (39.3%) were APOE e4 carriers. Higher GFAP concentrations were associated with increased odds for having cognitive impairment (GFAP z-score transformed: OR=2.233, 95% CI [1.609, 3.099], p<0.001; non-z-transformed: OR=1.004, 95% CI [1.002, 1.006], p<0.001). ROC analyses, comprising of GFAP and the above covariates, showed plasma GFAP discriminated the cognitively impaired from unimpaired (AUC=0.75) and was similar, but slightly superior, to plasma p-tau181 (AUC=0.74) and plasma NfL (AUC=0.74). A joint panel of the plasma markers had greatest discrimination accuracy (AUC=0.76). Linear regression analyses showed that higher GFAP levels were associated with worse performance on neuropsychological tests assessing global cognition, attention, executive functioning, episodic memory, and language abilities (ps<0.001) as well as higher CDR Sum of Boxes (p<0.001).
Conclusions:Higher plasma GFAP levels differentiated participants with cognitive impairment from those with normal cognition and were associated with worse performance on all neuropsychological tests assessed. GFAP had similar accuracy in detecting those with cognitive impairment compared with p-tau181 and NfL, however, a panel of all three biomarkers was optimal. These results support the utility of plasma GFAP in AD detection and suggest the pathological processes it represents might play an integral role in the pathogenesis of AD.
5 Antemortem Plasma GFAP Predicts Alzheimer’s Disease Neuropathological Changes
- Madeline Ally, Henrik Zetterberg, Kaj Blennow, Nicholas J. Ashton, Thomas K. Karikari, Hugo Aparicio, Michael A. Sugarman, Brandon Frank, Yorghos Tripodis, Brett Martin, Joseph N. Palmisano, Eric G. Steinberg, Irene Simkina, Lindsay Farrer, Gyungah Jun, Katherine W. Turk, Andrew E. Budson, Maureen K. O’Connor, Rhoda Au, Wei Qiao Qiu, Lee E. Goldstein, Ronald Killiany, Neil W. Kowall, Robert A. Stern, Jesse Mez, Bertran R. Huber, Ann C. McKee, Thor D. Stein, Michael L. Alosco
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 409-410
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Objective:
Blood-based biomarkers offer a more feasible alternative to Alzheimer’s disease (AD) detection, management, and study of disease mechanisms than current in vivo measures. Given their novelty, these plasma biomarkers must be assessed against postmortem neuropathological outcomes for validation. Research has shown utility in plasma markers of the proposed AT(N) framework, however recent studies have stressed the importance of expanding this framework to include other pathways. There is promising data supporting the usefulness of plasma glial fibrillary acidic protein (GFAP) in AD, but GFAP-to-autopsy studies are limited. Here, we tested the association between plasma GFAP and AD-related neuropathological outcomes in participants from the Boston University (BU) Alzheimer’s Disease Research Center (ADRC).
Participants and Methods:This sample included 45 participants from the BU ADRC who had a plasma sample within 5 years of death and donated their brain for neuropathological examination. Most recent plasma samples were analyzed using the Simoa platform. Neuropathological examinations followed the National Alzheimer’s Coordinating Center procedures and diagnostic criteria. The NIA-Reagan Institute criteria were used for the neuropathological diagnosis of AD. Measures of GFAP were log-transformed. Binary logistic regression analyses tested the association between GFAP and autopsy-confirmed AD status, as well as with semi-quantitative ratings of regional atrophy (none/mild versus moderate/severe) using binary logistic regression. Ordinal logistic regression analyses tested the association between plasma GFAP and Braak stage and CERAD neuritic plaque score. Area under the curve (AUC) statistics from receiver operating characteristics (ROC) using predicted probabilities from binary logistic regression examined the ability of plasma GFAP to discriminate autopsy-confirmed AD status. All analyses controlled for sex, age at death, years between last blood draw and death, and APOE e4 status.
Results:Of the 45 brain donors, 29 (64.4%) had autopsy-confirmed AD. The mean (SD) age of the sample at the time of blood draw was 80.76 (8.58) and there were 2.80 (1.16) years between the last blood draw and death. The sample included 20 (44.4%) females, 41 (91.1%) were White, and 20 (44.4%) were APOE e4 carriers. Higher GFAP concentrations were associated with increased odds for having autopsy-confirmed AD (OR=14.12, 95% CI [2.00, 99.88], p=0.008). ROC analysis showed plasma GFAP accurately discriminated those with and without autopsy-confirmed AD on its own (AUC=0.75) and strengthened as the above covariates were added to the model (AUC=0.81). Increases in GFAP levels corresponded to increases in Braak stage (OR=2.39, 95% CI [0.71-4.07], p=0.005), but not CERAD ratings (OR=1.24, 95% CI [0.004, 2.49], p=0.051). Higher GFAP levels were associated with greater temporal lobe atrophy (OR=10.27, 95% CI [1.53,69.15], p=0.017), but this was not observed with any other regions.
Conclusions:The current results show that antemortem plasma GFAP is associated with non-specific AD neuropathological changes at autopsy. Plasma GFAP could be a useful and practical biomarker for assisting in the detection of AD-related changes, as well as for study of disease mechanisms.
Low vitamin B12 but not folate is associated with incident depressive symptoms in community-dwelling older adults: a 4-year longitudinal study
- Eamon J. Laird, Aisling M. O’Halloran, Anne M. Molloy, Martin Healy, Belinda Hernandez, Deirdre M. A. O’Connor, Rose A. Kenny, Robert Briggs
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- Journal:
- British Journal of Nutrition / Volume 130 / Issue 2 / 28 July 2023
- Published online by Cambridge University Press:
- 13 December 2021, pp. 268-275
- Print publication:
- 28 July 2023
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This was a longitudinal study utilising the Irish Longitudinal Study on Ageing (n 3849 aged ≥ 50 years) and investigated the relationship between blood plasma folate and B12 levels at baseline (wave 1) and incident depressive symptoms at 2 and 4 years (waves 2 and 3). A score ≥ 9 on the Center for Epidemiological Studies Depression Scale-8 at wave 2 or 3 was indicative of incident depressive symptoms. B12 status profiles (pmol/l) were defined as < 185, deficient low; 185 to < 258, low normal; > 258–601, normal and > 601 high. Folate status profiles (nmol/l) were defined as ≤ 10·0, deficient low; > 10–23·0, low normal; > 23·0–45·0, normal; >45·0, high. Logistic regression models were used to analyse the longitudinal associations. Both B12 and folate plasma concentrations were lower in the group with incident depressive symptoms v. non-depressed (folate: 21·4 v. 25·1 nmol/l; P = 0·0003; B12:315·7 v. 335·9 pmol/l; P = 0·0148). Regression models demonstrated that participants with deficient-low B12 status at baseline had a significantly higher likelihood of incident depression 4 years later (OR 1·51, 95 % CI 1·01, 2·27, P = 0·043). This finding remained robust after controlling for relevant covariates. No associations of folate status with incident depression were observed. Older adults with deficient-low B12 status had a 51 % increased likelihood of developing depressive symptoms over 4 years. The findings highlight the need to further explore the low-cost benefits of optimising vitamin B12 status for depression in older adults.
List of Contributors
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- By Jane Balme, Graeme Barker, James Blinkhorn, Sandra Bowdler, Christopher Clarkson, Richard Cosgrove, Iain Davidson, Robin Dennell, Anne Ford, Natalie R. Franklin, Ian Gilligan, Huw S. Groucutt, Phillip J. Habgood, Chris Hunt, Michelle C. Langley, Armand Salvador B. Mijares, M. J. Morwood, Sue O’Connor, Stephen Oppenheimer, Alfred F. Pawlik, Michael D. Petraglia, Anne Pike-Tay, Philip J. Piper, Martin Porr, Ryan J. Rabett, Wil Roebroeks, Glenn R. Summerhayes
- Edited by Robin Dennell, University of Exeter, Martin Porr, University of Western Australia, Perth
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- Book:
- Southern Asia, Australia, and the Search for Human Origins
- Published online:
- 05 February 2014
- Print publication:
- 24 February 2014, pp xi-xvi
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Late Bronze Age Pottery Production: Evidence from a 12th–11th century cal bc Settlement at Tinney's Lane, Sherborne, Dorset
- Joanne Best, Ann Woodward, Michael J. Allen, Gordon Cook, David Dungworth, Rowena Gale, Derek Hamilton, Lorrain Higbee, Julie Jones, Gill Juleff, Mary Lewis, Peter D. Marshall, Brendan O'Connor, Ian Riddler, Roger Taylor, Martin Tingle, Kerry Tyler
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- Journal:
- Proceedings of the Prehistoric Society / Volume 78 / 2012
- Published online by Cambridge University Press:
- 04 March 2013, pp. 207-261
- Print publication:
- 2012
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Excavations at Tinney's Lane, Sherborne in 2002 uncovered extensive evidence for Late Bronze Age settlement and pottery production, dating from a short time period probably within the 12th or 11th century cal bc. Well-preserved deposits of burnt stone, broken vessels, and burnt sherds, together with resulting debris redeposited in associated pits, were accompanied by a series of post-hole structures interpreted as round-houses and four-post settings. Environmental evidence in the form of charcoal, charred plant remains, and molluscs has provided important information concerning sources of fuel and water for pottery production as well as allowing a reconstruction of the local vegetation. Finds of fired clay, metal, stone, shale, flint, and bone include items from distant sources, informing topics such as site status and exchange, and include many categories of tools and equipment that would have been used within the pottery-making processes. Analysis of the spatial distribution of these finds amongst the structures and surviving layers of burning has allowed the definition of a series of industrial activity areas, each comprising one or more round-houses, a four-post structure, bonfire bases or pits used for firing, and other pits with specific related functions. Altogether the site has provided some of the best evidence for pottery production within prehistoric Britain.
Contributors
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- By Douglas L. Arnold, Laura J. Balcer, Amit Bar-Or, Sergio E. Baranzini, Frederik Barkhof, Robert A. Bermel, Francois A. Bethoux, Dennis N. Bourdette, Richard K. Burt, Peter A. Calabresi, Zografos Caramanos, Tanuja Chitnis, Stacey S. Cofield, Jeffrey A. Cohen, Nadine Cohen, Alasdair J. Coles, Devon Conway, Stuart D. Cook, Gary R. Cutter, Peter J. Darlington, Ann Dodds-Frerichs, Ranjan Dutta, Gilles Edan, Michelle Fabian, Franz Fazekas, Massimo Filippi, Elizabeth Fisher, Paulo Fontoura, Corey C. Ford, Robert J. Fox, Natasha Frost, Alex Z. Fu, Siegrid Fuchs, Kazuo Fujihara, Kristin M. Galetta, Jeroen J.G. Geurts, Gavin Giovannoni, Nada Gligorov, Ralf Gold, Andrew D. Goodman, Myla D. Goldman, Jenny Guerre, Stephen L. Hauser, Peter B. Imrey, Douglas R. Jeffery, Stephen E. Jones, Adam I. Kaplin, Michael W. Kattan, B. Mark Keegan, Kyle C. Kern, Zhaleh Khaleeli, Samia J. Khoury, Joep Killestein, Soo Hyun Kim, R. Philip Kinkel, Stephen C. Krieger, Lauren B. Krupp, Emmanuelle Le Page, David Leppert, Scott Litwiller, Fred D. Lublin, Henry F. McFarland, Joseph C. McGowan, Don Mahad, Jahangir Maleki, Ruth Ann Marrie, Paul M. Matthews, Francesca Milanetti, Aaron E. Miller, Deborah M. Miller, Xavier Montalban, Charity J. Morgan, Ichiro Nakashima, Sridar Narayanan, Avindra Nath, Paul W. O’Connor, Jorge R. Oksenberg, A. John Petkau, Michael D. Phillips, J. Theodore Phillips, Tammy Phinney, Sean J. Pittock, Sarah M. Planchon, Chris H. Polman, Alexander Rae-Grant, Stephen M. Rao, Stephen C. Reingold, Maria A. Rocca, Richard A. Rudick, Amber R. Salter, Paula Sandler, Jaume Sastre-Garriga, John R. Scagnelli, Dana J. Serafin, Lynne Shinto, Nancy L. Sicotte, Jack H. Simon, Per Soelberg Sørensen, Ryan E. Stagg, James M. Stankiewicz, Lael A. Stone, Amy Sullivan, Matthew Sutliff, Jessica Szpak, Alan J. Thompson, Bruce D. Trapp, Helen Tremlett, Maria Trojano, Orla Tuohy, Rhonda R. Voskuhl, Marc K. Walton, Mike P. Wattjes, Emmanuelle Waubant, Martin S. Weber, Howard L Weiner, Brian G. Weinshenker, Bianca Weinstock-Guttman, Jeffrey L. Winters, Jerry S. Wolinsky, Vijayshree Yadav, E. Ann Yeh, Scott S. Zamvil
- Edited by Jeffrey A. Cohen, Richard A. Rudick
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- Book:
- Multiple Sclerosis Therapeutics
- Published online:
- 05 December 2011
- Print publication:
- 20 October 2011, pp viii-xii
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Software-engineering challenges of building and deploying reusable problem solvers
- Martin J. O'Connor, Csongor Nyulas, Samson Tu, David L. Buckeridge, Anna Okhmatovskaia, Mark A. Musen
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Problem solving methods (PSMs) are software components that represent and encode reusable algorithms. They can be combined with representations of domain knowledge to produce intelligent application systems. A goal of research on PSMs is to provide principled methods and tools for composing and reusing algorithms in knowledge-based systems. The ultimate objective is to produce libraries of methods that can be easily adapted for use in these systems. Despite the intuitive appeal of PSMs as conceptual building blocks, in practice, these goals are largely unmet. There are no widely available tools for building applications using PSMs and no public libraries of PSMs available for reuse. This paper analyzes some of the reasons for the lack of widespread adoptions of PSM techniques and illustrate our analysis by describing our experiences developing a complex, high-throughput software system based on PSM principles. We conclude that many fundamental principles in PSM research are useful for building knowledge-based systems. In particular, the task–method decomposition process, which provides a means for structuring knowledge-based tasks, is a powerful abstraction for building systems of analytic methods. However, despite the power of PSMs in the conceptual modeling of knowledge-based systems, software engineering challenges have been seriously underestimated. The complexity of integrating control knowledge modeled by developers using PSMs with the domain knowledge that they model using ontologies creates a barrier to widespread use of PSM-based systems. Nevertheless, the surge of recent interest in ontologies has led to the production of comprehensive domain ontologies and of robust ontology-authoring tools. These developments present new opportunities to leverage the PSM approach.
5 - The Middle Bronze Age
- Edited by John Barrett, Richard J. Bradley, Martin T. Green
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- Book:
- Landscape, Monuments and Society
- Published online:
- 07 May 2010
- Print publication:
- 22 February 1991, pp 143-226
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Summary
Introduction
It is during the Middle Bronze Age in southern Britain that archaeological field evidence for settlement and cultivation becomes readily available for study. This evidence comprises earthwork enclosures and lynchet systems. Childe regarded the apparent changes in agricultural practices indicated by these field remains as representative of an ‘agricultural revolution’. He evoked a comparison between an earlier state where the ‘warriorherdsman's wife’ had ‘tilled a little wheat and barley with the hoe’, with the emergence of ‘villages of a size and permanence hitherto unprecedented in Britain’ and their accompanying field systems (Childe 1947, 186–9).
The distinction between a prehistoric archaeology dominated by burial and ceremonial monuments, and one dominated by settlement sites and the earthwork remains of cultivation is still drawn today (Bradley 1984, 160). The explanation for the apparent transformation needs careful consideration. At base, this distinction is partly a matter of archaeological visibility. Settlements and cultivation have occurred in all the periods since the Neolithic, and whilst writers such as Childe and Curwen regarded Neolithic and Early Bronze Age settlement to be of a non-permanent and shifting character associated with a heavily pastoral economy (Childe 1947; Curwen 1938), this view is at least questioned, if not totally rejected today. We must be certain of the processes which render settlement and agriculture so visible in our later prehistory and then set about explaining those processes. This will be the main theme of this chapter.
4 - The Early Bronze Age
- Edited by John Barrett, Richard J. Bradley, Martin T. Green
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- Book:
- Landscape, Monuments and Society
- Published online:
- 07 May 2010
- Print publication:
- 22 February 1991, pp 109-140
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Summary
Introduction
The rather traditional division drawn here between the Late Neolithic and Early Bronze Age is simply one of convenience. It allows us to focus upon the development of round barrows, the construction of which show an essential continuity with developments during the previous period. However, henge monuments are no longer constructed in our area, and the barrows evidence a monumentality with an almost exclusive emphasis upon the dead. It is the changing emphasis in the practices associated with monumentality which is the issue here, rather than a simple technological division in the artefact sequence (Fig. 4.1).
Burgess has suggested a series of period divisions for the second millennium be (Table 4.1) in which his Mount Pleasant Period (c. 2150–1700 be) sees the introduction of copper, and then the full adoption of bronze metallurgy (metal Stages I-IV), along with most of the ‘steps’ of Beaker development (n.d. [1980]; 1980, 71; 1986). Although there remain considerable doubts about the detail of the Beaker chronology in Britain (see Longworth in Wainwright 1979b, 90), it seems most likely that the main currency of this material pre-dates 1700 be. The Beaker and early metal finds from the region are discussed below and, although sparsely represented, they are likely to have been contemporary with the final history of the Wyke Down henge. It is also probable that they fall within the period of use of the Knowlton henges.