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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.
LO026: Outcomes of a provincial cardiac reperfusion strategy: a population-based, retrospective cohort study
- J. Cook, A. Carter, A. Travers, R. Brown, E. Cain, J. Swain, J. Jensen, J. Goldstein, T. Lee
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- Journal:
- Canadian Journal of Emergency Medicine / Volume 18 / Issue S1 / May 2016
- Published online by Cambridge University Press:
- 02 June 2016, pp. S38-S39
- Print publication:
- May 2016
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Introduction: Nova Scotia has a province wide reperfusion strategy for the treatment of patients presenting with acute ST-Elevation Myocardial Infarction (STEMI). Patients are referred for primary percutaneous coronary intervention (PPCI) if a first medical contact to device time can be achieved within 90 to 120 minutes; otherwise, fibrinolytic therapy is administered, as per guideline recommendations. Since 2011, Nova Scotian paramedics have been providing prehospital fibrinolysis (PHF) and prehospital catheterization (cath) lab activation for STEMI patients outside and within the PPCI catchment area, respectively. Patients who received fibrinolysis are transferred to a PCI facility if rescue PCI is required or if there are other indications for urgent intervention. This province wide approach is unique and the objective of this retrospective cohort study is to compare the impact of this approach on the primary outcome of 30-day mortality. Methods: For the study period, July 2011 to July 2013, STEMI patients who were diagnosed prehospital or in the ED who subsequently underwent reperfusion therapy were identified in the Emergency Health Services (EHS), Cardiovascular Information Systems (CVIS) and Cardiovascular Health Nova Scotia (CVHNS) databases. Baseline demographics and outcomes were then compared according to the treatment received: 1) PHF; 2) ED Fibrinolysis (EDF); 3) prehospital activated PPCI (EHS PPCI); and 4) ED activated PPCI (ED PPCI). Results: There were a total of 1107 STEMI patients identified during the study period, of whom 742 received lytic therapy (146 PHF; 596 EDF) and 332 underwent PPCI (202 EHS PPCI; 130 ED PPCI). Demographic variables were similar across the groups. The primary outcome of 30-day mortality was not significantly different across groups: 5 (3%) in PHF, 26 (4%) in EDF, 8 (4%) in EHS to PPCI and 2 (2%) in ED to PPCI. The number of rescue PCIs was 28 (19%) in PHF and 102 (17%) in EDF. Other outcomes (key timestamps) are pending. Conclusion: Our results show that the 30-day mortality was lowest for patients undergoing PPCI and slightly less for patients receiving pre-hospital fibrinolytic compared to those receiving ED fibrinolytic with no difference in the proportion requiring subsequent rescue PCI. The majority of patients in rural areas received EDF as opposed to PHF; pending results will show if this represents a delay in patient presentation after symptom onset.
Contributors
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- By Nozomi Akanuma, Gonzalo Alarcón, R. Arunachalam, Sarah H. Bernard, Frank M. C. Besag, Istvan Bodi, Stephen Brown, Franz Brunnhuber, Antonella Cerquiglini, J. Helen Cross, R. Shane Delamont, Archana Desurkar, Lee Drummond, Rona Eade, Robert D. C. Elwes, Bidi Evans, Peter Fenwick, Colin D. Ferrie, Paul L. Furlong, Laura H. Goldstein, Sally Gomersall, Sushma Goyal, Jane Hanna, Yvonne Hart, Dominic C. Heaney, Graham E. Holder, Mrinalini Honavar, Elaine Hughes, Jozef M. Jarosz, John G. R. Jefferys, Jane Juler, Mathias Koepp, Michalis Koutroumanidis, Maureen Lahiff, Louis Lemieux, David McCormick, Brian Meldrum, John D. C. Mellers, Nicholas Moran, John Moriarty, Robin G. Morris, Nandini Mullatti, Lina Nashef, Jennifer Nightingale, T. J. von Oertzen, Corina O'Neill, Philip N. Patsalos, Stella Pearson, Charles E. Polkey, Ronit Pressler, Edward H. Reynolds, Mark P. Richardson, Leone Ridsdale, Robert Robinson, Greg Rogers, Euan M. Ross, Richard P. Selway, Stefano Seri, Simeran Sharma, Graeme J. Sills, Andrew Simmons, Shiri Spector, Mark Stevenson, Jade N. Thai, Brian Toone, Antonio Valentín, Nuria T. Villagra, Matthew Walker, William Whitehouse
- Edited by Gonzalo Alarcón, King's College London, Antonio Valentín, King's College London
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- Book:
- Introduction to Epilepsy
- Published online:
- 05 July 2012
- Print publication:
- 26 April 2012, pp xii-xv
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Contributors
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- By Dmitri Bezinover, Ira Todd Cohen, Garret Choby, Kimberly E. Fenton, David Goldenberg, Goldstein Scott, Brian W. Grose, Michael K. Hurst, Zara Karparvar, Jodie E. Landis, Thomas K. Lee, Jonathan D McGinn, Raymond Maguire, Daryn H Moller, Slawomir Oleszak, Michael Ondik, Steven L. Orebaugh, Sophie R. Pestieau, Shaji Poovathoor, Eric Posner, Leonard Pott, Diego Preciado, Elliot Regenbogen, Elias B Rizk, Ghassan J. Samara, Peggy A Seidman, Elizabeth H Sinz, MS Dana Stauffer, BS Joanne Stene, John Stene, Jay B. Tuchman, Yvonne Tsui, James Vosswinkel, Alison Wilson, Margaret Wojnar, Robert Yellon
- Edited by Peggy A. Seidman, Stony Brook University, State University of New York, Elizabeth H. Sinz, Pennsylvania State University, David Goldenberg, Pennsylvania State University
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- Book:
- Tracheotomy Management
- Published online:
- 25 October 2011
- Print publication:
- 20 October 2011, pp viii-xi
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Fully coupled resonant-triad interaction in an adverse-pressure-gradient boundary layer
- M. E. Goldstein, Sang Soo Lee
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- Journal:
- Journal of Fluid Mechanics / Volume 245 / December 1992
- Published online by Cambridge University Press:
- 26 April 2006, pp. 523-551
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The nonlinear resonant-triad interaction, proposed by Raetz (1959). Craik (1971), and others for a Blasius boundary layer, is analysed here for an adverse-pressure-gradient boundary layer. We assume that the adverse pressure gradient is in some sense weak and, therefore, that the instability growth rate is small. This ensures that there is a well-defined critical layer located somewhere within the flow and that the nonlinear interaction is effectively confined to that layer. The initial interaction is of the parametric resonance type, even when the modal amplitudes are all of the same order. This means that the oblique instability waves exhibit faster than exponential growth and that the growth rate of the two-dimensional mode remains linear. However, the interaction and the resulting growth rates become fully coupled, once oblique-mode amplitudes become sufficiently large, but the coupling terms are now quartic, rather than quadratic as in the Craik (1971) analysis. More importantly, however, new nonlinear interactions, which were not present in the Craik-type analyses, now come into play. These interactions eventually have a dominant effect on the instability wave development.