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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.
Neutron Star Extreme Matter Observatory: A kilohertz-band gravitational-wave detector in the global network
- Part of
- K. Ackley, V. B. Adya, P. Agrawal, P. Altin, G. Ashton, M. Bailes, E. Baltinas, A. Barbuio, D. Beniwal, C. Blair, D. Blair, G. N. Bolingbroke, V. Bossilkov, S. Shachar Boublil, D. D. Brown, B. J. Burridge, J. Calderon Bustillo, J. Cameron, H. Tuong Cao, J. B. Carlin, S. Chang, P. Charlton, C. Chatterjee, D. Chattopadhyay, X. Chen, J. Chi, J. Chow, Q. Chu, A. Ciobanu, T. Clarke, P. Clearwater, J. Cooke, D. Coward, H. Crisp, R. J. Dattatri, A. T. Deller, D. A. Dobie, L. Dunn, P. J. Easter, J. Eichholz, R. Evans, C. Flynn, G. Foran, P. Forsyth, Y. Gai, S. Galaudage, D. K. Galloway, B. Gendre, B. Goncharov, S. Goode, D. Gozzard, B. Grace, A. W. Graham, A. Heger, F. Hernandez Vivanco, R. Hirai, N. A. Holland, Z. J. Holmes, E. Howard, E. Howell, G. Howitt, M. T. Hübner, J. Hurley, C. Ingram, V. Jaberian Hamedan, K. Jenner, L. Ju, D. P. Kapasi, T. Kaur, N. Kijbunchoo, M. Kovalam, R. Kumar Choudhary, P. D. Lasky, M. Y. M. Lau, J. Leung, J. Liu, K. Loh, A. Mailvagan, I. Mandel, J. J. McCann, D. E. McClelland, K. McKenzie, D. McManus, T. McRae, A. Melatos, P. Meyers, H. Middleton, M. T. Miles, M. Millhouse, Y. Lun Mong, B. Mueller, J. Munch, J. Musiov, S. Muusse, R. S. Nathan, Y. Naveh, C. Neijssel, B. Neil, S. W. S. Ng, V. Oloworaran, D. J. Ottaway, M. Page, J. Pan, M. Pathak, E. Payne, J. Powell, J. Pritchard, E. Puckridge, A. Raidani, V. Rallabhandi, D. Reardon, J. A. Riley, L. Roberts, I. M. Romero-Shaw, T. J. Roocke, G. Rowell, N. Sahu, N. Sarin, L. Sarre, H. Sattari, M. Schiworski, S. M. Scott, R. Sengar, D. Shaddock, R. Shannon, J. SHI, P. Sibley, B. J. J. Slagmolen, T. Slaven-Blair, R. J. E. Smith, J. Spollard, L. Steed, L. Strang, H. Sun, A. Sunderland, S. Suvorova, C. Talbot, E. Thrane, D. Töyrä, P. Trahanas, A. Vajpeyi, J. V. van Heijningen, A. F. Vargas, P. J. Veitch, A. Vigna-Gomez, A. Wade, K. Walker, Z. Wang, R. L. Ward, K. Ward, S. Webb, L. Wen, K. Wette, R. Wilcox, J. Winterflood, C. Wolf, B. Wu, M. Jet Yap, Z. You, H. Yu, J. Zhang, J. Zhang, C. Zhao, X. Zhu
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- Journal:
- Publications of the Astronomical Society of Australia / Volume 37 / 2020
- Published online by Cambridge University Press:
- 05 November 2020, e047
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Gravitational waves from coalescing neutron stars encode information about nuclear matter at extreme densities, inaccessible by laboratory experiments. The late inspiral is influenced by the presence of tides, which depend on the neutron star equation of state. Neutron star mergers are expected to often produce rapidly rotating remnant neutron stars that emit gravitational waves. These will provide clues to the extremely hot post-merger environment. This signature of nuclear matter in gravitational waves contains most information in the 2–4 kHz frequency band, which is outside of the most sensitive band of current detectors. We present the design concept and science case for a Neutron Star Extreme Matter Observatory (NEMO): a gravitational-wave interferometer optimised to study nuclear physics with merging neutron stars. The concept uses high-circulating laser power, quantum squeezing, and a detector topology specifically designed to achieve the high-frequency sensitivity necessary to probe nuclear matter using gravitational waves. Above 1 kHz, the proposed strain sensitivity is comparable to full third-generation detectors at a fraction of the cost. Such sensitivity changes expected event rates for detection of post-merger remnants from approximately one per few decades with two A+ detectors to a few per year and potentially allow for the first gravitational-wave observations of supernovae, isolated neutron stars, and other exotica.
Developmental programming of skeletal muscle phenotype/metabolism
- T. C. W. Markham, R. M. Latorre, P. G. Lawlor, C. J. Ashton, L. B. McNamara, R. Natter, A. Rowlerson, N. C. Stickland
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Skeletal muscle is a highly dynamic and malleable tissue that is able to adapt to different stimuli placed upon it, both during gestation and after birth, ultimately resulting in anatomical changes to muscle fibre composition. Variation in nutrient supply throughout gestation is common, whether in livestock or in the human. The specific effects of maternal nutrition on foetal development are at the forefront of scientific research. However, results describing how different maternal feeding strategies affect skeletal muscle fibre development in the offspring are not fully consistent, even where the same time windows during gestation have been examined. The aim of this study is to determine the effects of increased maternal nutrition (above the recommended levels) on the Musculus semitendinosus phenotype of progeny. In all, 24 pregnant sows were assigned to one of four feeding regimes during gestation; T1 (control group): 30 MJ digestible energy per day (MJ DE/day) throughout gestation, T2: same as that for T1 but increased to 60 MJ DE/day from 25 to 50 days of gestation (dg), T3: same as that for T1 but increased to 60 MJ DE/day from 50 to 80 dg, T4: same as that for T1 but increased nutrition to 60 MJ DE/day from 25 to 80 dg. Light- and heavy-weight littermate pairs of the same sex were selected at birth and individually fed to slaughter (c. 158 days). Histochemical and immunohistochemical staining were used to identify the predominantly oxidative (deep) and less oxidative (superficial) regions of the M. semitendinosus, and to determine total fibre number and proportions of fibre types. The results demonstrate that increased maternal nutrition alters skeletal muscle phenotype in the offspring by changing fibre-type proportions, leading to an increased oxidative capacity due to an increase in Type IIA fibres. No change in total muscle area, total muscle fibre number, or fibre cross-sectional area is observed. The precise molecular mechanism(s) by which these findings occur is being investigated.
Looking Backward, Looking Forward: MLA Members Speak
- April Alliston, Elizabeth Ammons, Jean Arnold, Nina Baym, Sandra L. Beckett, Peter G. Beidler, Roger A. Berger, Sandra Bermann, J.J. Wilson, Troy Boone, Alison Booth, Wayne C. Booth, James Phelan, Marie Borroff, Ihab Hassan, Ulrich Weisstein, Zack Bowen, Jill Campbell, Dan Campion, Jay Caplan, Maurice Charney, Beverly Lyon Clark, Robert A. Colby, Thomas C. Coleman III, Nicole Cooley, Richard Dellamora, Morris Dickstein, Terrell Dixon, Emory Elliott, Caryl Emerson, Ann W. Engar, Lars Engle, Kai Hammermeister, N. N. Feltes, Mary Anne Ferguson, Annie Finch, Shelley Fisher Fishkin, Jerry Aline Flieger, Norman Friedman, Rosemarie Garland-Thomson, Sandra M. Gilbert, Laurie Grobman, George Guida, Liselotte Gumpel, R. K. Gupta, Florence Howe, Cathy L. Jrade, Richard A. Kaye, Calhoun Winton, Murray Krieger, Robert Langbaum, Richard A. Lanham, Marilee Lindemann, Paul Michael Lützeler, Thomas J. Lynn, Juliet Flower MacCannell, Michelle A. Massé, Irving Massey, Georges May, Christian W. Hallstein, Gita May, Lucy McDiarmid, Ellen Messer-Davidow, Koritha Mitchell, Robin Smiles, Kenyatta Albeny, George Monteiro, Joel Myerson, Alan Nadel, Ashton Nichols, Jeffrey Nishimura, Neal Oxenhandler, David Palumbo-Liu, Vincent P. Pecora, David Porter, Nancy Potter, Ronald C. Rosbottom, Elias L. Rivers, Gerhard F. Strasser, J. L. Styan, Marianna De Marco Torgovnick, Gary Totten, David van Leer, Asha Varadharajan, Orrin N. C. Wang, Sharon Willis, Louise E. Wright, Donald A. Yates, Takayuki Yokota-Murakami, Richard E. Zeikowitz, Angelika Bammer, Dale Bauer, Karl Beckson, Betsy A. Bowen, Stacey Donohue, Sheila Emerson, Gwendolyn Audrey Foster, Jay L. Halio, Karl Kroeber, Terence Hawkes, William B. Hunter, Mary Jambus, Willard F. King, Nancy K. Miller, Jody Norton, Ann Pellegrini, S. P. Rosenbaum, Lorie Roth, Robert Scholes, Joanne Shattock, Rosemary T. VanArsdel, Alfred Bendixen, Alarma Kathleen Brown, Michael J. Kiskis, Debra A. Castillo, Rey Chow, John F. Crossen, Robert F. Fleissner, Regenia Gagnier, Nicholas Howe, M. Thomas Inge, Frank Mehring, Hyungji Park, Jahan Ramazani, Kenneth M. Roemer, Deborah D. Rogers, A. LaVonne Brown Ruoff, Regina M. Schwartz, John T. Shawcross, Brenda R. Silver, Andrew von Hendy, Virginia Wright Wexman, Britta Zangen, A. Owen Aldridge, Paula R. Backscheider, Roland Bartel, E. M. Forster, Milton Birnbaum, Jonathan Bishop, Crystal Downing, Frank H. Ellis, Roberto Forns-Broggi, James R. Giles, Mary E. Giles, Susan Blair Green, Madelyn Gutwirth, Constance B. Hieatt, Titi Adepitan, Edgar C. Knowlton, Jr., Emanuel Mussman, Sally Todd Nelson, Robert O. Preyer, David Diego Rodriguez, Guy Stern, James Thorpe, Robert J. Wilson, Rebecca S. Beal, Joyce Simutis, Betsy Bowden, Sara Cooper, Wheeler Winston Dixon, Tarek el Ariss, Richard Jewell, John W. Kronik, Wendy Martin, Stuart Y. McDougal, Hugo Méndez-Ramírez, Ivy Schweitzer, Armand E. Singer, G. Thomas Tanselle, Tom Bishop, Mary Ann Caws, Marcel Gutwirth, Christophe Ippolito, Lawrence D. Kritzman, James Longenbach, Tim McCracken, Wolfe S. Molitor, Diane Quantic, Gregory Rabassa, Ellen M. Tsagaris, Anthony C. Yu, Betty Jean Craige, Wendell V. Harris, J. Hillis Miller, Jesse G. Swan, Helene Zimmer-Loew, Peter Berek, James Chandler, Hanna K. Charney, Philip Cohen, Judith Fetterley, Herbert Lindenberger, Julia Reinhard Lupton, Maximillian E. Novak, Richard Ohmann, Marjorie Perloff, Mark Reynolds, James Sledd, Harriet Turner, Marie Umeh, Flavia Aloya, Regina Barreca, Konrad Bieber, Ellis Hanson, William J. Hyde, Holly A. Laird, David Leverenz, Allen Michie, J. Wesley Miller, Marvin Rosenberg, Daniel R. Schwarz, Elizabeth Welt Trahan, Jean Fagan Yellin
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- Journal:
- PMLA / Publications of the Modern Language Association of America / Volume 115 / Issue 7 / December 2000
- Published online by Cambridge University Press:
- 23 October 2020, pp. 1986-2078
- Print publication:
- December 2000
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Ancestry of plant MADS-box genes revealed by bryophyte (Physcomitrella patens) homologues
- N. T. KROGAN, N. W. ASHTON
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- The New Phytologist / Volume 147 / Issue 3 / September 2000
- Published online by Cambridge University Press:
- 23 October 2000, pp. 505-517
- Print publication:
- September 2000
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Three MADS-box cDNA clones and two corresponding genomic sequences (gDNAs) have been isolated from the bryophyte Physcomitrella patens and sequenced. Our findings indicate that the genes may be expressed in a tissue- or age-specific manner, and that expression of one of them is regulated by an alternative splicing mechanism. Conceptual translation of the clones reveals that the encoded MADS-domain proteins have the typical plant-domain pattern (MIKC). Additionally, there is a high degree of conservation of intron number and positions between angiosperm MADS-box genes and the moss loci. These observations confirm the homology of moss and higher plant MADS-box genes. We conclude that the MIKC pattern evolved in MADS-box genes after the separation of the plant lineage from that of fungi and animals, and that it must have been present in the common ancestor of mosses, ferns and seed plants. Therefore it evolved at least 400 million yr ago. Phylogenetic analysis of a large subset of the sequenced plant MADS-box genes, incorporating those from P. patens, indicates that the bryophyte genes are not orthologues of spermatophyte genes belonging to any of the well recognized higher plant gene subfamilies. This conclusion accords well with reports that the known fern MADS-box genes also comprise subfamilies distinct from those of higher plants. Therefore we tentatively propose that the gene duplication and diversification events that created the MADS-box gene subfamilies, discernible in extant angiosperm and other spermatophyte groups, occurred after separation of the moss and fern lineages from the lineage which produced the higher plants.
Energy expenditure during heavy work and its interaction with body weight
- P. Haggarty, M. E. Valencia, G. McNeill, N. L. Gonzales, S. Y. Moya, A. Pinelli, L. Quihui, M. S. Saucedo, J. Esparza, J. Ashton, E. Milne, W. P. T. James
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- Journal:
- British Journal of Nutrition / Volume 77 / Issue 3 / March 1997
- Published online by Cambridge University Press:
- 09 March 2007, pp. 359-373
- Print publication:
- March 1997
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The present study was designed to investigate the interaction between body weight and energy expenditure in well-nourished individuals. Energy expenditure was determined during a 10 d highly controlled work programme in apparently well-nourished adult male construction workers with a wide range of body weights (mean weight: 63·9 (SD 11·0, range 46·7-80·1) kg, mean BMI: 22·5 (SD 3·8, range 16·7-28·9) kg/m2). Total energy expenditure (mean: 12·68 (SE 0·73) MJ/d or 1·78 (SE 0·07) x BMR) was determined using doubly-labelled water and the energy costs of work activities by Oxylog. The energy expenditure during work (mean: 5·75 (SE 0·29) MJ/day or 3·48 (SE 0·09) x BMR) was estimated from the energy costs of individual tasks and the time spent in those tasks. The energy expenditure during discretionary time (mean: 4·37 (SE 0·58) MJ/d or 1·49 (SE 0·17) x BMR) was calculated by subtracting occupation and sleep expenditure (taken as1 x BMR) from total expenditure. Food intake and discretionary time allocation were recorded by the subjects. The energy expenditure in the programmed work activities (expressed as a multiple of BMR) showed a significant increase (P=0·035) with increasing body weight, suggesting that the assumed constancy of BMR multiples across a wide range of body weights may not be valid. This assertion was supported by theoretical calculations based on empirically derived equations. In order to avoid errors which could be interpreted as metabolic ‘adaptation’ it may be necessary to take account of body weight when using the BMR-multiple approach to estimate energy requirements at low body weights.