126 results on '"Masters C"'
Search Results
2. Multiomics Blood-Based Biomarkers Predict Alzheimer’s Predementia with High Specificity in a Multicentric Cohort Study
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Souchet, B., Michaïl, A., Heuillet, M., Dupuy-Gayral, A., Haudebourg, E., Pech, C., Berthemy, A., Autelitano, F., Billoir, B., Domoto-Reilly, K., Fowler, C., Grabowski, T., Jayadev, S., Masters, C. L., and Braudeau, Jérôme
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- 2024
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3. Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU): Trial Satisfaction and Attitudes towards Future Clinical Trials
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Liu, Haiyan, Li, J., Ziegemeier, E., Adams, S., McDade, E., Clifford, D. B., Cao, Y., Wang, G., Li, Y., Mills, S. L., Santacruz, A. M., Belyew, S., Grill, J. D., Snider, B. J., Mummery, C. J., Surti, G., Hannequin, D., Wallon, D., Berman, S. B., Jimenez-Velazquez, I. Z., Roberson, E. D., van Dyck, C. H., Honig, L. S., Sanchez-Valle, R., Brooks, W. S., Gauthier, S., Galasko, D., Masters, C. L., Brosch, J., Hsiung, G.-Y. R., Jayadev, S., Formaglio, M., Masellis, M., Clarnette, R., Pariente, J., Dubois, B., Pasquier, F., Bateman, R. J., and Llibre-Guerra, Jorge J.
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- 2024
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4. Two-Year Prognostic Utility of Plasma p217+tau across the Alzheimer’s Continuum
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Feizpour, A., Doré, V., Doecke, J. D., Saad, Z. S., Triana-Baltzer, G., Slemmon, R., Maruff, P., Krishnadas, N., Bourgeat, P., Huang, K., Fowler, C., Rainey-Smith, S. R., Bush, A. I., Ward, L., Robertson, J., Martins, R. N., Masters, C. L., Villemagne, V. L., Fripp, J., Kolb, H. C., and Rowe, Christopher C.
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- 2023
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5. Can We Use Blood Biomarkers as Entry Criteria and for Monitoring Drug Treatment Effects in Clinical Trials? A Report from the EU/US CTAD Task Force
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Angioni, D., Hansson, O., Bateman, R. J., Rabe, C., Toloue, M., Braunstein, J. B., Agus, S., Sims, J. R., Bittner, T., Carrillo, M. C., Fillit, H., Masters, C. L., Salloway, S., Aisen, P., Weiner, M., Vellas, B., Gauthier, S., Abushakra, Susan, Afshar, Mohammad, Alam, John, Algeciras-Schimnich, Alicia, Andrieu, Sandrine, Ballard, Clive, Baruch, Amos, Batrla, Richard, Baudler, Monika, Bell, Joanne, Bozeat, Sasha, Brooks, Dawn, Brooks, Tricia, Bullain, Szofia, Burmeister, Jan, Cho, Min, Collins, Emily, Cook, Gavin, Cummings, Jeffrey, Dague, Chris, De Santi, Susan, Doody, Rachelle, Dunn, Billy, Egan, Michael, Eriksson, Sven, Esquivel, Rianne, Fagan, Tom, Ferrell, Phyllis, Gallagher, Michela, Grönblad, Anna-Kaija, Hains, Avis, Hampel, Harald, Hefting, Nanco, Hendrix, Suzanne, Ho, Carole, Hu, Helen, Ismail, Zahinoor, Jones, Daryl, Kinney, Gene, Kinnon, Paul, Kurzman, Ricky, Lannfelt, Lars, Lawson, John, LeBastard, Nathalie, Legrand, Valérie, Lewandowski, Nicole, Lim, Carine, Lyketsos, Costantine, Masterman, Donna, Lu, Ming, Mintun, Mark, Molinuevo, José Luis, Monteiro, Cecilia, Navia, Bradford, Odergren, Tomas, Osswald, Gunilla, Penny, Lewis, Pontecorvo, Michael, Porsteinsson, Anton, Raman, Rema, Respondek, Gesine, Reyderman, Larisa, Rogers, Sharon, Rosenberg, Paul, Rosenzweig-Lipson, Sharon, Roskey, Mark, Carrie, Rubel, Saad, Ziad, Schindler, Rachel, Selkoe, Dennis, Shulman, Melanie, Sink, Kaycee, Sipe, Lisa, Skovronsky, Daniel, Somers, Elizabeth, Soto, Maria, Streffer, Johannes, Such, Pedro, Suhy, Joyce, Touchon, Jacques, Vandijck, Manu, White, Anne, Wilson, David, Zago, Wagner, and Zhou, Jin
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- 2023
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6. A Conformational Variant of p53 (U-p53AZ) as Blood-Based Biomarker for the Prediction of the Onset of Symptomatic Alzheimer’s Disease
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Piccirella, Simona, Van Neste, L., Fowler, C., Masters, C. L., Fripp, J., Doecke, J. D., Xiong, C., Uberti, D., and Kinnon, P.
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- 2022
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7. Accuracy of TrUE-Net in comparison to established white matter hyperintensity segmentation methods: An independent validation study.
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Strain, JF, Rahmani, M, Dierker, D, Owen, C, Jafri, H, Vlassenko, AG, Womack, K, Fripp, J, Tosun, D, Benzinger, TLS, Weiner, M, Masters, C, Lee, J-M, Morris, JC, Goyal, MS, ADOPIC and ADNI Investigators, Strain, JF, Rahmani, M, Dierker, D, Owen, C, Jafri, H, Vlassenko, AG, Womack, K, Fripp, J, Tosun, D, Benzinger, TLS, Weiner, M, Masters, C, Lee, J-M, Morris, JC, Goyal, MS, and ADOPIC and ADNI Investigators
- Abstract
White matter hyperintensities (WMH) are nearly ubiquitous in the aging brain, and their topography and overall burden are associated with cognitive decline. Given their numerosity, accurate methods to automatically segment WMH are needed. Recent developments, including the availability of challenge data sets and improved deep learning algorithms, have led to a new promising deep-learning based automated segmentation model called TrUE-Net, which has yet to undergo rigorous independent validation. Here, we compare TrUE-Net to six established automated WMH segmentation tools, including a semi-manual method. We evaluated the techniques at both global and regional level to compare their ability to detect the established relationship between WMH burden and age. We found that TrUE-Net was highly reliable at identifying WMH regions with low false positive rates, when compared to semi-manual segmentation as the reference standard. TrUE-Net performed similarly or favorably when compared to the other automated techniques. Moreover, TrUE-Net was able to detect relationships between WMH and age to a similar degree as the reference standard semi-manual segmentation at both the global and regional level. These results support the use of TrUE-Net for identifying WMH at the global or regional level, including in large, combined datasets.
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- 2024
8. Association Between Cognitive Function and Clustered Cardiovascular Risk of Metabolic Syndrome in Older Adults at Risk of Cognitive Decline
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Lai, Michelle M. Y., Ames, D. J., Cox, K. L., Ellis, K. A., Sharman, M. J., Hepworth, G., Desmond, P., Cyarto, E. V., Szoeke, C., Martins, R., Masters, C. L., and Lautenschlager, N. T.
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- 2020
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9. Application of the NIA-AA Research Framework: Towards a Biological Definition of Alzheimer’s Disease using Cerebrospinal Fluid Biomarkers in the AIBL Study
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Burnham, Samantha C., Coloma, P. M., Li, Q.-X., Collins, S., Savage, G., Laws, S., Doecke, J., Maruff, P., Martins, R. N., Ames, D., Rowe, C. C., Masters, C. L., and Villemagne, V. L.
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- 2019
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10. Imaging of tau deposits in adults with Niemann-Pick type C disease: a case-control study
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Villemagne, Victor L., Velakoulis, D., Doré, V., Bozinoski, S., Masters, C. L., Rowe, C. C., and Walterfang, Mark
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- 2019
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11. 12415 Surgical Management of Undescended Gonads for Androgen Insensitivity Syndrome.
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Gonzalez Pena, TI, Cook, EN, Masters, C, Roach, M, and Anderson, T
- Abstract
To demonstrate a surgical technique for management of undescended testicular tissue for patients with complete androgen insensitivity syndrome. Narrated surgical presentation. Androgen insensitivity syndrome (AIS) is an X-linked genetic disorder characterized by peripheral androgen resistance due to androgen receptor mutations in subjects with 46 XY karyotype. Despite normal testicular development, the testes are often retained in the abdomen or inguinal canal. Gonadectomy is usually recommended because undescended testicular tissue presents increased risk of malignant transformation after puberty. Video footage and operative photos were used with obtained consent from one patient undergoing laparoscopic bilateral gonadectomy. The patient underwent laparoscopic bilateral gonadectomy. N/A. AIS is rare genetic disorder in which androgen receptor mutation leads to female secondary sex characteristics despite testes formation. For complete AIS, gonadectomy is recommended post-puberty to decrease risk of malignant transformation of testicular tissue. [ABSTRACT FROM AUTHOR]
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- 2024
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12. Are Maternal Self-Reports of Social Difficulties Apparent in Interactions with their Children?
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Kellerman, A. M., primary, Masters, C., additional, and Schwichtenberg, A. J., additional
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- 2022
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13. Prognostic serum miRNA biomarkers associated with Alzheimer’s disease shows concordance with neuropsychological and neuroimaging assessment
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Cheng, L, Doecke, J D, Sharples, R A, Villemagne, V L, Fowler, C J, Rembach, A, Martins, R N, Rowe, C C, Macaulay, S L, Masters, C L, and Hill, A F
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- 2015
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14. Dietary patterns and cognitive decline in an Australian study of ageing
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Gardener, S L, Rainey-Smith, S R, Barnes, M B, Sohrabi, H R, Weinborn, M, Lim, Y Y, Harrington, K, Taddei, K, Gu, Y, Rembach, A, Szoeke, C, Ellis, K A, Masters, C L, Macaulay, S L, Rowe, C C, Ames, D, Keogh, J B, Scarmeas, N, and Martins, R N
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- 2015
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15. Combining 18F-florbetaben Aβ imaging and MRI in mild cognitive impairment: OR38
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Ong, K, Villemagne, V, Bahar-Fuchs, A, Lamb, F, Chételat, G, Raniga, P, Mulligan, R, Salvado, O, Putz, B, Roth, K, Masters, C, Reininger, C, and Rowe, C
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- 2016
16. Cerebrovascular disease, Alzheimerʼs disease biomarkers and longitudinal cognitive decline: OR2
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Yates, P A, Villemagne, V L, Ames, D, Masters, C L, Martins, R N, Desmond, P, Burnham, S, Maruff, P, Ellis, K A, and Rowe, C C
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- 2016
17. APOE and BDNF polymorphisms moderate amyloid β-related cognitive decline in preclinical Alzheimerʼs disease
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Lim, Y Y, Villemagne, V L, Laws, S M, Pietrzak, R H, Snyder, P J, Ames, D, Ellis, K A, Harrington, K, Rembach, A, Martins, R N, Rowe, C C, Masters, C L, and Maruff, P
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- 2015
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18. Plasma amyloid-beta levels in a pre-symptomatic Dutch-type hereditary cerebral amyloid angiopathy pedigree: A cross-sectional and longitudinal investigation
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Chatterjee, P., Tegg, M., Pedrini, S., Fagan, A., Xiong, C., Singh, A., Taddei, K., Gardener, S., Masters, C., Schofield, P., Multhaup, G., Benzinger, T., Morris, J., Bateman, R., Greenberg, S., van Buchem, M., Stoops, E., Vanderstichele, H., Teunissen, C., Hankey, G., Wermer, M., Sohrabi, H., Martins, R.N., the Dominantly Inherited Alzheimer Network, Chatterjee, P., Tegg, M., Pedrini, S., Fagan, A., Xiong, C., Singh, A., Taddei, K., Gardener, S., Masters, C., Schofield, P., Multhaup, G., Benzinger, T., Morris, J., Bateman, R., Greenberg, S., van Buchem, M., Stoops, E., Vanderstichele, H., Teunissen, C., Hankey, G., Wermer, M., Sohrabi, H., Martins, R.N., and the Dominantly Inherited Alzheimer Network
- Abstract
Plasma amyloid-beta (Aβ) has long been investigated as a blood biomarker candidate for Cerebral Amyloid Angiopathy (CAA), however previous findings have been inconsistent which could be attributed to the use of less sensitive assays. This study investigates plasma Aβ alterations between pre-symptomatic Dutch-type hereditary CAA (D-CAA) mutation-carriers (MC) and non-carriers (NC) using two Aβ measurement platforms. Seventeen pre-symptomatic members of a D-CAA pedigree were assembled and followed up 3–4 years later (NC = 8; MC = 9). Plasma Aβ1-40 and Aβ1-42 were cross-sectionally and longitudinally analysed at baseline (T1) and follow-up (T2) and were found to be lower in MCs compared to NCs, cross-sectionally after adjusting for covariates, at both T1(Aβ1-40: p = 0.001; Aβ1-42: p = 0.0004) and T2 (Aβ1-40: p = 0.001; Aβ1-42: p = 0.016) employing the Single Molecule Array (Simoa) platform, however no significant differences were observed using the xMAP platform. Further, pairwise longitudinal analyses of plasma Aβ1-40 revealed decreased levels in MCs using data from the Simoa platform (p = 0.041) and pairwise longitudinal analyses of plasma Aβ1-42 revealed decreased levels in MCs using data from the xMAP platform (p = 0.041). Findings from the Simoa platform suggest that plasma Aβ may add value to a panel of biomarkers for the diagnosis of pre-symptomatic CAA, however, further validation studies in larger sample sets are required.
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- 2021
19. RP25- Sigmoid methodology allows early prediction of cognitive decline towards Alzheimer's disease across several cognitive domains
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Cespedes, M., Gillis, C., Maruff, P., Maserejian, N., Fowler, C., Rainey-Smith, S., Villemagne, V., Rowe, C., Martins, R., Masters, C., Doecke, J., Cespedes, M., Gillis, C., Maruff, P., Maserejian, N., Fowler, C., Rainey-Smith, S., Villemagne, V., Rowe, C., Martins, R., Masters, C., and Doecke, J.
- Abstract
Background: Clinical trials in Alzheimer’s disease (AD) depend on clinical endpoints that may lack sensitivity to the cognitive changes that characterize the disease prior to dementia diagnosis. Consequently, trials designed to determine whether new drugs can forestall dementia or prevent cognitive decline prior to onset of AD dementia will require outcomes measures that are sensitive to cognitive changes earlier in the disease. Objectives: The objective of this work was to identify individuals whose cognitive scores progress more rapidly (“accelerators”) from those whose cognition does not reach this same level over the same time period (“non-accelerators”). The specific aim was to assess the MMSE, CDR-SB and seven different cognitive composite scores to examine 1) their ability to cluster accelerators and non- accelerators, 2) which cognitive scores can be used as strong predictors of cognitive change, and 3) the proportion agreement of progression classification within specific subgroups of AD pathology. This process was entirely data driven in that it was performed without using the formal AIBL clinical classification to inform disease stage. Methods: Using longitudinal data from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing, seven cognitive composite scores (the AIBL PACC score (CVLT-II, LMII, DSC & MMSE), attention and processing speed (DSC & total digit span), episodic memory (delayed recall, LMII & RCFT30), executive function (verbal fluency & category switching), language (BNT & verbal fluency [D-KEFS]), recognition (recognition CVLT-II & RCFT), visuospatial function (RCFT copy & clock along) along with MMSE and CDR-SB from 144 months of AIBL were selected from all participants with at least three time points (at baseline: total N=1269; 973 Cognitively Normal (CN), 143 with Mild Cognitive Impairment (MCI), 153 with AD). Using the mathematical properties of a proposed sigmoidal function, “cognitive turning points” are defined to all
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- 2021
20. A Conformational Variant of p53 (U-p53AZ) as Blood-Based Biomarker for the Prediction of the Onset of Symptomatic Alzheimer's Disease.
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Piccirella, Simona, Van Neste, L., Fowler, C., Masters, C. L., Fripp, J., Doecke, J. D., Xiong, C., Uberti, D., and Kinnon, P.
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- 2022
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21. Amyloid and tau pathology associations with personality traits, neuropsychiatric symptoms, and cognitive lifestyle in the preclinical phases of sporadic and autosomal dominant Alzheimer’s disease
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Pichet Binette, A., Vachon-Presseau, É., Morris, J., Bateman, R., Benzinger, T., Collins, D.L., Poirier, J., Breitner, J.C.S., Villeneuve, S., Allegri, R., Amtashar, F., Berman, S., Bodge, C., Brandon, S., Brooks, W., Buck, Jill, Buckles, V., Chea, S., Chhatwal, J., Chrem, P., Chui, H., Cinco, J., Clifford, J., Cruchaga, C., D‘Mello, M., Donahue, T., Douglas, J., Edigo, N., Erekin-Taner, N., Fagan, A., Farlow, M., Farrar, A., Feldman, H., Flynn, G., Fox, N., Franklin, E., Fujii, H., Gant, C., Gardener, S., Ghetti, B., Goate, A., Goldman, J., Gordon, B., Graff-Radford, N., Gray, J., Gurney, J., Hassenstab, J., Hirohara, M., Holtzman, D., Hornbeck, R., DiBari, S.H., Ikeuchi, T., Ikonomovic, S., Jerome, G., Jucker, M., Karch, C., Kasuga, K., Kawarabayashi, T., Klunk, W., Koeppe, R., Kuder-Buletta, E., Laske, C., Lee, J-H, Levin, J., Marcus, D., Martins, R., Mason, N.S., Masters, C., Maue-Dreyfus, D., McDade, E., Montoya, L., Mori, H., Nagamatsu, A., Neimeyer, K., Noble, J., Norton, J., Perrin, R., Raichle, M., Ringman, J., Roh, J.H., Salloway, S., Schofield, P., Shimada, H., Shiroto, T., Shoji, M., Sigurdson, W., Sohrabi, H., Sparks, P., Suzuki, K., Swisher, L., Taddei, K., Wang, J., Wang, P., Weiner, M., Wolfsberger, M., Xiong, C., Xu, X., Tam, A., Labonté, A., Faubert, A-M, Mathieu, A., Madjar, C., Carrier, C.E., Dansereau, C., Kazazian, C., Lepage, C., Picard, C., Maillet, D., Michaud, D., Couture, D., Dea, D., Cuello, C., Barkun, A., Evans, A., Courcot, B., Tardif, C., Debacker, C., Jack, C.R., Fontaine, D., Knopman, D.S., Maultaup, G., Near, J., Leoutsakos, J-M, Maltais, J-R, Brandt, J., Pruessner, J., Morris, J.C., Cheewakriengkrai, L., Münter, L-M, Collins, L., Chakravarty, M., Sager, M.A., Dauar-Tedeschi, M., Eisenberg, M., Rajah, N., Aisen, P., Toussaint, J., Rosa-Neto, P., Bellec, P., Kostopoulos, P., Etienne, P., Tariot, P.N., Orban, P., Sperling, R.A., Hoge, R., Thomas, R.G., Gauthier, S., Craft, S., Montine, T.J., Nair, V., Bohbot, V., Venugopalan, V., Fonov, V., Ituria-Medina, Y., Khachaturian, Z.S., Teigner, E., Anthal, E., Yu, E., Ferdinand, F., Pogossova, G., Mayrand, G., Duclair, G., Gagné, G., Newbold-Fox, H., Leppert, I., Vallée, I., Vogel, J.W., Tremblay-Mercier, J., Frenette, J., Frappier, J., Kat, J., Miron, J., Wan, K., Mahar, L., Carmo, L., Théroux, L., Dadar, M., Dufour, M., Lafaille-Magnan, M-E, Appleby, M., Savard, M., Tuwaig, M., Petkova, M., Rioux, P., Meyer, P-F, El-Khoury, R., Gordon, R., Giles, R., Das, S., Wang, S., Tabrizi, S., Mathotaarachchi, S., Dubuc, S., Lee, T., Beaudry, T., Gervais, V., Pagé, V., Gonneaud, J., Ayranci, G., Pascoal, T.A., Desautels, R., Benbouhoud, F., Saint-Fort, E.F., Verfaillie, S.C.J., Farzin, S., Salaciak, A., Tullo, S., Vachon-Presseau, E., Daoust, L-A, Köbe, T., Spreng, N., McSweeney, M., Nilsson, N., Pishnamazi, M., Bedetti, C., Pichet Binette, A., Vachon-Presseau, É., Morris, J., Bateman, R., Benzinger, T., Collins, D.L., Poirier, J., Breitner, J.C.S., Villeneuve, S., Allegri, R., Amtashar, F., Berman, S., Bodge, C., Brandon, S., Brooks, W., Buck, Jill, Buckles, V., Chea, S., Chhatwal, J., Chrem, P., Chui, H., Cinco, J., Clifford, J., Cruchaga, C., D‘Mello, M., Donahue, T., Douglas, J., Edigo, N., Erekin-Taner, N., Fagan, A., Farlow, M., Farrar, A., Feldman, H., Flynn, G., Fox, N., Franklin, E., Fujii, H., Gant, C., Gardener, S., Ghetti, B., Goate, A., Goldman, J., Gordon, B., Graff-Radford, N., Gray, J., Gurney, J., Hassenstab, J., Hirohara, M., Holtzman, D., Hornbeck, R., DiBari, S.H., Ikeuchi, T., Ikonomovic, S., Jerome, G., Jucker, M., Karch, C., Kasuga, K., Kawarabayashi, T., Klunk, W., Koeppe, R., Kuder-Buletta, E., Laske, C., Lee, J-H, Levin, J., Marcus, D., Martins, R., Mason, N.S., Masters, C., Maue-Dreyfus, D., McDade, E., Montoya, L., Mori, H., Nagamatsu, A., Neimeyer, K., Noble, J., Norton, J., Perrin, R., Raichle, M., Ringman, J., Roh, J.H., Salloway, S., Schofield, P., Shimada, H., Shiroto, T., Shoji, M., Sigurdson, W., Sohrabi, H., Sparks, P., Suzuki, K., Swisher, L., Taddei, K., Wang, J., Wang, P., Weiner, M., Wolfsberger, M., Xiong, C., Xu, X., Tam, A., Labonté, A., Faubert, A-M, Mathieu, A., Madjar, C., Carrier, C.E., Dansereau, C., Kazazian, C., Lepage, C., Picard, C., Maillet, D., Michaud, D., Couture, D., Dea, D., Cuello, C., Barkun, A., Evans, A., Courcot, B., Tardif, C., Debacker, C., Jack, C.R., Fontaine, D., Knopman, D.S., Maultaup, G., Near, J., Leoutsakos, J-M, Maltais, J-R, Brandt, J., Pruessner, J., Morris, J.C., Cheewakriengkrai, L., Münter, L-M, Collins, L., Chakravarty, M., Sager, M.A., Dauar-Tedeschi, M., Eisenberg, M., Rajah, N., Aisen, P., Toussaint, J., Rosa-Neto, P., Bellec, P., Kostopoulos, P., Etienne, P., Tariot, P.N., Orban, P., Sperling, R.A., Hoge, R., Thomas, R.G., Gauthier, S., Craft, S., Montine, T.J., Nair, V., Bohbot, V., Venugopalan, V., Fonov, V., Ituria-Medina, Y., Khachaturian, Z.S., Teigner, E., Anthal, E., Yu, E., Ferdinand, F., Pogossova, G., Mayrand, G., Duclair, G., Gagné, G., Newbold-Fox, H., Leppert, I., Vallée, I., Vogel, J.W., Tremblay-Mercier, J., Frenette, J., Frappier, J., Kat, J., Miron, J., Wan, K., Mahar, L., Carmo, L., Théroux, L., Dadar, M., Dufour, M., Lafaille-Magnan, M-E, Appleby, M., Savard, M., Tuwaig, M., Petkova, M., Rioux, P., Meyer, P-F, El-Khoury, R., Gordon, R., Giles, R., Das, S., Wang, S., Tabrizi, S., Mathotaarachchi, S., Dubuc, S., Lee, T., Beaudry, T., Gervais, V., Pagé, V., Gonneaud, J., Ayranci, G., Pascoal, T.A., Desautels, R., Benbouhoud, F., Saint-Fort, E.F., Verfaillie, S.C.J., Farzin, S., Salaciak, A., Tullo, S., Vachon-Presseau, E., Daoust, L-A, Köbe, T., Spreng, N., McSweeney, M., Nilsson, N., Pishnamazi, M., and Bedetti, C.
- Abstract
Background Major prevention trials for Alzheimer’s disease (AD) are now focusing on multidomain lifestyle interventions. However, the exact combination of behavioral factors related to AD pathology remains unclear. In 2 cohorts of cognitively unimpaired individuals at risk of AD, we examined which combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle (years of education or lifetime cognitive activity) related to the pathological hallmarks of AD, amyloid-β, and tau deposits. Methods A total of 115 older adults with a parental or multiple-sibling family history of sporadic AD (PREVENT-AD [PRe-symptomatic EValuation of Experimental or Novel Treatments for AD] cohort) underwent amyloid and tau positron emission tomography and answered several questionnaires related to behavioral attributes. Separately, we studied 117 mutation carriers from the DIAN (Dominant Inherited Alzheimer Network) study group cohort with amyloid positron emission tomography and behavioral data. Using partial least squares analysis, we identified latent variables relating amyloid or tau pathology with combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle. Results In PREVENT-AD, lower neuroticism, neuropsychiatric burden, and higher education were associated with less amyloid deposition (p = .014). Lower neuroticism and neuropsychiatric features, along with higher measures of openness and extraversion, were related to less tau deposition (p = .006). In DIAN, lower neuropsychiatric burden and higher education were also associated with less amyloid (p = .005). The combination of these factors accounted for up to 14% of AD pathology. Conclusions In the preclinical phase of both sporadic and autosomal dominant AD, multiple behavioral features were associated with AD pathology. These results may suggest potential pathways by which multidomain interventions might help delay AD onset or progression.
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- 2020
22. A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease
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Barthélemy, N.R., Li, Y., Joseph-Mathurin, N., Gordon, B.A., Hassenstab, J., Benzinger, T.L.S., Buckles, V., Fagan, A.M., Perrin, R.J., Goate, A.M., Morris, J.C., Karch, C.M., Xiong, C., Allegri, R., Mendez, P.C., Berman, S.B., Ikeuchi, T., Mori, H., Shimada, H., Shoji, M., Suzuki, K., Noble, J., Farlow, M., Chhatwal, J., Graff-Radford, N.R., Salloway, S., Schofield, P.R., Masters, C.L., Martins, R.N., O’Connor, A., Fox, N.C., Levin, J., Jucker, M., Gabelle, A., Lehmann, S., Sato, C., Bateman, R.J., McDade, E., Bateman, R., Bechara, J., Benzinger, T., Berman, S., Bodge, C., Brandon, S., Brooks, W., Buck, J., Chea, S., Chrem Mendez, P., Chui, H., Cinco, J., Clifford, J., Cruchaga, C., Donahue, T., Douglas, J., Edigo, N., Erekin-Taner, N., Fagan, A., Fitzpatrick, C., Flynn, G., Fox, N., Franklin, E., Fujii, H., Gant, C., Gardener, S., Ghetti, B., Goate, A., Goldman, J., Gordon, B., Graff-Radford, N., Gray, J., Groves, A., Hoechst-Swisher, L., Holtzman, D., Hornbeck, R., Houeland DiBari, S., Ikonomovic, S., Jerome, G., Karch, C., Kasuga, K., Kawarabayashi, T., Klunk, W., Koeppe, R., Kuder-Buletta, E., Laske, C., Lee, J-H, Martins, R., Mason, N.S., Masters, C., Maue-Dreyfus, D., Morris, J., Nagamatsu, A., Neimeyer, K., Norton, J., Perrin, R., Raichle, M., Renton, A., Ringman, J., Roh, J.H., Schofield, P., Sigurdson, W., Sohrabi, H., Sparks, P., Taddei, K., Wang, P., Xu, X., Barthélemy, N.R., Li, Y., Joseph-Mathurin, N., Gordon, B.A., Hassenstab, J., Benzinger, T.L.S., Buckles, V., Fagan, A.M., Perrin, R.J., Goate, A.M., Morris, J.C., Karch, C.M., Xiong, C., Allegri, R., Mendez, P.C., Berman, S.B., Ikeuchi, T., Mori, H., Shimada, H., Shoji, M., Suzuki, K., Noble, J., Farlow, M., Chhatwal, J., Graff-Radford, N.R., Salloway, S., Schofield, P.R., Masters, C.L., Martins, R.N., O’Connor, A., Fox, N.C., Levin, J., Jucker, M., Gabelle, A., Lehmann, S., Sato, C., Bateman, R.J., McDade, E., Bateman, R., Bechara, J., Benzinger, T., Berman, S., Bodge, C., Brandon, S., Brooks, W., Buck, J., Chea, S., Chrem Mendez, P., Chui, H., Cinco, J., Clifford, J., Cruchaga, C., Donahue, T., Douglas, J., Edigo, N., Erekin-Taner, N., Fagan, A., Fitzpatrick, C., Flynn, G., Fox, N., Franklin, E., Fujii, H., Gant, C., Gardener, S., Ghetti, B., Goate, A., Goldman, J., Gordon, B., Graff-Radford, N., Gray, J., Groves, A., Hoechst-Swisher, L., Holtzman, D., Hornbeck, R., Houeland DiBari, S., Ikonomovic, S., Jerome, G., Karch, C., Kasuga, K., Kawarabayashi, T., Klunk, W., Koeppe, R., Kuder-Buletta, E., Laske, C., Lee, J-H, Martins, R., Mason, N.S., Masters, C., Maue-Dreyfus, D., Morris, J., Nagamatsu, A., Neimeyer, K., Norton, J., Perrin, R., Raichle, M., Renton, A., Ringman, J., Roh, J.H., Schofield, P., Sigurdson, W., Sohrabi, H., Sparks, P., Taddei, K., Wang, P., and Xu, X.
- Abstract
Development of tau-based therapies for Alzheimer’s disease requires an understanding of the timing of disease-related changes in tau. We quantified the phosphorylation state at multiple sites of the tau protein in cerebrospinal fluid markers across four decades of disease progression in dominantly inherited Alzheimer’s disease. We identified a pattern of tau staging where site-specific phosphorylation changes occur at different periods of disease progression and follow distinct trajectories over time. These tau phosphorylation state changes are uniquely associated with structural, metabolic, neurodegenerative and clinical markers of disease, and some (p-tau217 and p-tau181) begin with the initial increases in aggregate amyloid-β as early as two decades before the development of aggregated tau pathology. Others (p-tau205 and t-tau) increase with atrophy and hypometabolism closer to symptom onset. These findings provide insights into the pathways linking tau, amyloid-β and neurodegeneration, and may facilitate clinical trials of tau-based treatments.
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- 2020
23. The molecular origins of Alzheimer’s disease: When does it start and what strategies for primary prevention?
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Masters, C., primary
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- 2019
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24. Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s disease
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Preische, O., Schultz, S.A., Apel, A., Kuhle, J., Kaeser, S.A., Barro, C., Gräber, S., Kuder-Buletta, E., LaFougere, C., Laske, C., Vöglein, J., Levin, J., Masters, C.L., Martins, R., Schofield, P.R., Rossor, M.N., Graff-Radford, N.R., Salloway, S., Ghetti, B., Ringman, J.M., Noble, J.M., Chhatwal, J., Goate, A.M., Benzinger, T.L.S., Morris, J.C., Bateman, R.J., Wang, G., Fagan, A.M., McDade, E.M., Gordon, B.A., Jucker, M., Allegri, R., Amtashar, F., Bateman, R., Benzinger, T., Berman, S., Bodge, C., Brandon, S., Brooks, W., Buck, J., Buckles, V., Chea, S., Chrem, P., Chui, H., Cinco, J., Clifford, J., Cruchaga, C., D’Mello, M., Donahue, T., Douglas, J., Edigo, N., Erekin-Taner, N., Fagan, A., Farlow, M., Farrar, A., Feldman, H., Flynn, G., Fox, N., Franklin, E., Fujii, H., Gant, C., Gardener, S., Goate, A., Goldman, J., Gordon, B., Graff-Radford, N., Gray, J., Gurney, J., Hassenstab, J., Hirohara, M., Holtzman, D., Hornbeck, R., Houeland DiBari, S., Ikeuchi, T., Ikonomovic, S., Jerome, G., Karch, C., Kasuga, K., Kawarabayashi, T., Klunk, W., Koeppe, R., Lee, J-H, Marcus, D., Mason, N.S., Masters, C., Maue-Dreyfus, D., McDade, E., Montoya, L., Mori, H., Morris, J., Nagamatsu, A., Neimeyer, K., Noble, J., Norton, J., Perrin, R., Raichle, M., Ringman, J., Roh, J-H, Schofield, P., Shimada, H., Shiroto, T., Shoji, M., Sigurdson, W., Sohrabi, H., Sparks, P., Suzuki, K., Swisher, L., Taddei, K., Wang, J., Wang, P., Weiner, M., Wolfsberger, M., Xiong, C., Xu, X., Preische, O., Schultz, S.A., Apel, A., Kuhle, J., Kaeser, S.A., Barro, C., Gräber, S., Kuder-Buletta, E., LaFougere, C., Laske, C., Vöglein, J., Levin, J., Masters, C.L., Martins, R., Schofield, P.R., Rossor, M.N., Graff-Radford, N.R., Salloway, S., Ghetti, B., Ringman, J.M., Noble, J.M., Chhatwal, J., Goate, A.M., Benzinger, T.L.S., Morris, J.C., Bateman, R.J., Wang, G., Fagan, A.M., McDade, E.M., Gordon, B.A., Jucker, M., Allegri, R., Amtashar, F., Bateman, R., Benzinger, T., Berman, S., Bodge, C., Brandon, S., Brooks, W., Buck, J., Buckles, V., Chea, S., Chrem, P., Chui, H., Cinco, J., Clifford, J., Cruchaga, C., D’Mello, M., Donahue, T., Douglas, J., Edigo, N., Erekin-Taner, N., Fagan, A., Farlow, M., Farrar, A., Feldman, H., Flynn, G., Fox, N., Franklin, E., Fujii, H., Gant, C., Gardener, S., Goate, A., Goldman, J., Gordon, B., Graff-Radford, N., Gray, J., Gurney, J., Hassenstab, J., Hirohara, M., Holtzman, D., Hornbeck, R., Houeland DiBari, S., Ikeuchi, T., Ikonomovic, S., Jerome, G., Karch, C., Kasuga, K., Kawarabayashi, T., Klunk, W., Koeppe, R., Lee, J-H, Marcus, D., Mason, N.S., Masters, C., Maue-Dreyfus, D., McDade, E., Montoya, L., Mori, H., Morris, J., Nagamatsu, A., Neimeyer, K., Noble, J., Norton, J., Perrin, R., Raichle, M., Ringman, J., Roh, J-H, Schofield, P., Shimada, H., Shiroto, T., Shoji, M., Sigurdson, W., Sohrabi, H., Sparks, P., Suzuki, K., Swisher, L., Taddei, K., Wang, J., Wang, P., Weiner, M., Wolfsberger, M., Xiong, C., and Xu, X.
- Abstract
Neurofilament light chain (NfL) is a promising fluid biomarker of disease progression for various cerebral proteopathies. Here we leverage the unique characteristics of the Dominantly Inherited Alzheimer Network and ultrasensitive immunoassay technology to demonstrate that NfL levels in the cerebrospinal fluid (n = 187) and serum (n = 405) are correlated with one another and are elevated at the presymptomatic stages of familial Alzheimer’s disease. Longitudinal, within-person analysis of serum NfL dynamics (n = 196) confirmed this elevation and further revealed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels (that is, 16.2 versus 6.8 years before the estimated symptom onset). Serum NfL rate of change peaked in participants converting from the presymptomatic to the symptomatic stage and was associated with cortical thinning assessed by magnetic resonance imaging, but less so with amyloid-β deposition or glucose metabolism (assessed by positron emission tomography). Serum NfL was predictive for both the rate of cortical thinning and cognitive changes assessed by the Mini–Mental State Examination and Logical Memory test. Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer’s disease, which supports its potential utility as a clinically useful biomarker.
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- 2019
25. Klotho allele status is not associated with Aß and APOE e4–related cognitive decline in preclinical Alzheimer's disease
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Porter, T., Burnham, S., Milicic, L., Savage, G., Maruff, P., Lim, Y., Ames, D., Masters, C., Martins, R., Rainey-Smith, S., Rowe, C., Salvado, O., Groth, David, Verdile, Giuseppe, Villemagne, V., Laws, S., Porter, T., Burnham, S., Milicic, L., Savage, G., Maruff, P., Lim, Y., Ames, D., Masters, C., Martins, R., Rainey-Smith, S., Rowe, C., Salvado, O., Groth, David, Verdile, Giuseppe, Villemagne, V., and Laws, S.
- Abstract
© 2019 Elsevier Inc. The longevity gene Klotho (KL), specifically the functional KL-VS variant, has previously been associated with cognition and rates of cognitive decline. This study aimed to determine whether KL-VS associations with cognition were observable in preclinical Alzheimer's disease (AD). The study also aimed to determine whether there was a combined influence of KL-VS, neocortical amyloid-ß (Aß) burden, and carriage of the apolipoprotein E (APOE) e4 allele on cognitive decline. This study involved 581 Aß-imaged, cognitively normal older adults, enrolled in the Australian Imaging, Biomarkers and Lifestyle Study of Aging. Linear mixed effects models revealed no significant associations between KL-VS and cognitive decline independently or in combination with Aß burden and APOE e4 genotype. Overall, previous associations reported between KL-VS and cognitive decline are not observed at the preclinical stages of AD. Furthermore, the results do not support the hypothesis that KL-VS has a modifying effect on Aß burden and APOE e4–driven cognitive decline in preclinical AD.
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- 2019
26. A Polygenic Risk Score Derived From Episodic Memory Weighted Genetic Variants Is Associated With Cognitive Decline in Preclinical Alzheimer's Disease
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Porter, T., Burnham, S., Savage, G., Lim, Y., Maruff, P., Milicic, L., Peretti, M., Ames, D., Masters, C., Martins, R., Rainey-Smith, S., Rowe, C., Salvado, O., Taddei, K., Groth, David, Verdile, Giuseppe, Villemagne, V., Laws, Simon, Porter, T., Burnham, S., Savage, G., Lim, Y., Maruff, P., Milicic, L., Peretti, M., Ames, D., Masters, C., Martins, R., Rainey-Smith, S., Rowe, C., Salvado, O., Taddei, K., Groth, David, Verdile, Giuseppe, Villemagne, V., and Laws, Simon
- Abstract
Studies of Alzheimer's disease risk-weighted polygenic risk scores (PRSs) for cognitive performance have reported inconsistent associations. This inconsistency is particularly evident when PRSs are assessed independent of APOE genotype. As such, the development and assessment of phenotype-specific weightings to derive PRSs for cognitive decline in preclinical AD is warranted. To this end a episodic memory-weighted PRS (emPRS) was derived and assessed against decline in cognitive performance in 226 healthy cognitively normal older adults with high brain Aβ-amyloid burden participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. The effect size for decline in a verbal episodic memory was determined individually for 27 genetic variants in a reference sample (n = 151). These were then summed to generate a emPRS either including APOE (emPRSc̅APOE) or excluding APOE (emPRSs̅APOE ). Resultant emPRS were then evaluated, in a test sample (n = 75), against decline in global cognition, verbal episodic memory and a pre-Alzheimer's cognitive composite (AIBL-PACC) over 7.5 years. The mean (SD) age of the 226 participants was 72.2 (6.6) years and 116 (51.3%) were female. Reference and test samples did not differ significantly demographically. Whilst no association of emPRSs were observed with baseline cognition, the emPRSc̅ APOE was associated with longitudinal global cognition (-0.237, P = 0.0002), verbal episodic memory (-0.259, P = 0.00003) and the AIBL-PACC (-0.381, P = 0.02). The emPRSs̅ APOE was also associated with global cognition (-0.169, P = 0.021) and verbal episodic memory (-0.208, P = 0.004). Stratification by APOE ε4 revealed that the association between the emPRS and verbal episodic memory was limited to carriage of no ε4 or one ε4 allele. This was also observed for global cognition. The emPRS and rates of decline in AIBL-PACC were associated in those carrying one ε4 allele. Overall, the described novel emPRS has utility for the prediction of
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- 2018
27. KIBRA is associated with accelerated cognitive decline and hippocampal atrophy in APOE ε4-positive cognitively normal adults with high Aß-amyloid burden
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Porter, T., Burnham, S., Doré, V., Savage, G., Bourgeat, P., Begemann, K., Milicic, L., Ames, D., Bush, A., Maruff, P., Masters, C., Rowe, C., Rainey-Smith, S., Martins, R., Groth, David, Verdile, Giuseppe, Villemagne, V., Laws, S., Porter, T., Burnham, S., Doré, V., Savage, G., Bourgeat, P., Begemann, K., Milicic, L., Ames, D., Bush, A., Maruff, P., Masters, C., Rowe, C., Rainey-Smith, S., Martins, R., Groth, David, Verdile, Giuseppe, Villemagne, V., and Laws, S.
- Abstract
© 2018 The Author(s). A single nucleotide polymorphism, rs17070145, in the KIdney and BRAin expressed protein (KIBRA) gene has been associated with cognition and hippocampal volume in cognitively normal (CN) individuals. However, the impact of rs17070145 on longitudinal cognitive decline and hippocampal atrophy in CN adults at greatest risk of developing Alzheimer's disease is unknown. We investigated the impact rs17070145 has on the rate of cognitive decline and hippocampal atrophy over six years in 602 CN adults, with known brain Aß-amyloid levels and whether there is an interactive effect with APOE genotype. We reveal that whilst limited independent effects of KIBRA genotype were observed, there was an interaction with APOE in CN adults who presented with high Aß-amyloid levels across study duration. In comparison to APOE ?4-ve individuals carrying the rs17070145-T allele, significantly faster rates of cognitive decline (global, p = 0.006; verbal episodic memory, p = 0.004), and hippocampal atrophy (p = 0.04) were observed in individuals who were APOE ?4 + ve and did not carry the rs17070145-T allele. The observation of APOE effects in only non-carriers of the rs17070145-T allele, in the presence of high Aß-amyloid suggest that carriers of the rs17070145-T allele are conferred a level of resilience to the detrimental effects of high Aß-amyloid and APOE ?4.
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- 2018
28. Trajectories of depressive and anxiety symptoms in older adults: a 6-year prospective cohort study
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Holmes, S., Esterlis, I., Mazure, C., Lim, Y., Ames, D., Rainey-Smith, S., Fowler, C., Ellis, K., Martins, R., Salvado, O., Doré, V., Villemagne, V., Rowe, C., Laws, Simon, Masters, C., Pietrzak, R., Maruff, P., Holmes, S., Esterlis, I., Mazure, C., Lim, Y., Ames, D., Rainey-Smith, S., Fowler, C., Ellis, K., Martins, R., Salvado, O., Doré, V., Villemagne, V., Rowe, C., Laws, Simon, Masters, C., Pietrzak, R., and Maruff, P.
- Abstract
Copyright © 2017 John Wiley & Sons, Ltd. Objective: Depressive and anxiety symptoms are common in older adults, significantly affect quality of life, and are risk factors for Alzheimer's disease. We sought to identify the determinants of predominant trajectories of depressive and anxiety symptoms in cognitively normal older adults. Method: Four hundred twenty-three older adults recruited from the general community underwent Aß positron emission tomography imaging, apolipoprotein and brain-derived neurotrophic factor genotyping, and cognitive testing at baseline and had follow-up assessments. All participants were cognitively normal and free of clinical depression at baseline. Latent growth mixture modeling was used to identify predominant trajectories of subthreshold depressive and anxiety symptoms over 6 years. Binary logistic regression analysis was used to identify baseline predictors of symptomatic depressive and anxiety trajectories. Results: Latent growth mixture modeling revealed two predominant trajectories of depressive and anxiety symptoms: a chronically elevated trajectory and a low, stable symptom trajectory, with almost one in five participants falling into the elevated trajectory groups. Male sex (relative risk ratio (RRR) = 3.23), lower attentional function (RRR = 1.90), and carriage of the brain-derived neurotrophic factor Val66Met allele in women (RRR = 2.70) were associated with increased risk for chronically elevated depressive symptom trajectory. Carriage of the apolipoprotein epsilon 4 allele (RRR = 1.92) and lower executive function in women (RRR = 1.74) were associated with chronically elevated anxiety symptom trajectory. Conclusion: Our results indicate distinct and sex-specific risk factors linked to depressive and anxiety trajectories, which may help inform risk stratification and management of these symptoms in older adults at risk for Alzheimer's disease. Copyright © 2017 John Wiley & Sons, Ltd.
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- 2018
29. Utility of an Alzheimer's Disease Risk-Weighted Polygenic Risk Score for Predicting Rates of Cognitive Decline in Preclinical Alzheimer's Disease: A Prospective Longitudinal Study.
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Porter, T., Burnham, S., Milicic, L., Savage, G., Maruff, P., Lim, Y., Li, Q., Ames, D., Masters, C., Rainey-Smith, S., Rowe, C., Salvado, O., Groth, D., Verdile, Giuseppe, Villemagne, V., Laws, S., AIBL Research Group, Porter, T., Burnham, S., Milicic, L., Savage, G., Maruff, P., Lim, Y., Li, Q., Ames, D., Masters, C., Rainey-Smith, S., Rowe, C., Salvado, O., Groth, D., Verdile, Giuseppe, Villemagne, V., Laws, S., and AIBL Research Group
- Abstract
BACKGROUND: With the exception of APOE, genetic variants associated with increased Alzheimer's disease (AD) risk are characterized by small effect sizes. Polygenic risk scores (PRS) have shown utility in predicting AD risk; however, their utility for predicting decline in cognition at preclinical stages of AD is poorly understood. OBJECTIVE: To validate associations of a 22-variant AD-risk-weighted PRS with AD risk and related biomarkers and to assess its utility to predict cognitive decline. METHODS: The PRS was evaluated with respect to brain amyloid-ß (Aß) burden, cerebrospinal fluid (CSF) Aß42, total-tau, and phospho-tau, and decline in cognition in 643 (570 cognitively normal (CN), 73 AD) PET-imaged participants from the longitudinal Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing. Cognition was assessed using three composite measures; global cognition, verbal episodic memory, and a Pre-Alzheimer's Cognitive Composite (PACC). RESULTS: PRS, both with and without APOE, were positively correlated with brain Aß burden, CSF total-tau, and phospho-tau in CN older adults. Further, in CN biomarker positive (Aßhigh) participants, significant associations were observed with baseline and longitudinal cognition. However, this association was not observed after the removal of APOE. Partitioning the PRS into quartiles revealed that the PRS associations with cognitive decline in Aßhigh CN older adults is due to a saturating effect of APOE genotype. CONCLUSIONS: An AD-risk-weighted PRS is associated with cognitive decline in CN older adults. However, this association is absent when APOE genotype is excluded from the PRS, suggesting that associations with cognitive decline in this model of polygenic risk are driven by APOE genotype alone. Further research is needed to define appropriate PRSs with greater utility for predicting preclinical AD cognitive decline.
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- 2018
30. Alzheimer's Disease: A Journey from Amyloid Peptides and Oxidative Stress, to Biomarker Technologies and Disease Prevention Strategies-Gains from AIBL and DIAN Cohort Studies
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Martins, R., Villemagne, V., Sohrabi, H., Chatterjee, P., Shah, T., Verdile, Giuseppe, Fraser, P., Taddei, K., Gupta, V., Rainey-Smith, S., Hone, E., Pedrini, S., Lim, W., Martins, I., Frost, S., Gupta, S., O'Bryant, S., Rembach, A., Ames, D., Ellis, K., Fuller, S., Brown, B., Gardener, S., Fernando, B., Bharadwaj, Prashant, Burnham, S., Laws, S., Barron, A., Goozee, K., Wahjoepramono, E., Asih, P., Doecke, J., Salvado, O., Bush, A., Rowe, C., Gandy, S., Masters, C., Martins, R., Villemagne, V., Sohrabi, H., Chatterjee, P., Shah, T., Verdile, Giuseppe, Fraser, P., Taddei, K., Gupta, V., Rainey-Smith, S., Hone, E., Pedrini, S., Lim, W., Martins, I., Frost, S., Gupta, S., O'Bryant, S., Rembach, A., Ames, D., Ellis, K., Fuller, S., Brown, B., Gardener, S., Fernando, B., Bharadwaj, Prashant, Burnham, S., Laws, S., Barron, A., Goozee, K., Wahjoepramono, E., Asih, P., Doecke, J., Salvado, O., Bush, A., Rowe, C., Gandy, S., and Masters, C.
- Abstract
© 2018-IOS Press and the authors. All rights reserved. Worldwide there are over 46 million people living with dementia, and this number is expected to double every 20 years reaching about 131 million by 2050. The cost to the community and government health systems, as well as the stress on families and carers is incalculable. Over three decades of research into this disease have been undertaken by several research groups in Australia, including work by our original research group in Western Australia which was involved in the discovery and sequencing of the amyloid-β peptide (also known as Aβ or A4 peptide) extracted from cerebral amyloid plaques. This review discusses the journey from the discovery of the Aβ peptide in Alzheimer's disease (AD) brain to the establishment of pre-clinical AD using PET amyloid tracers, a method now serving as the gold standard for developing peripheral diagnostic approaches in the blood and the eye. The latter developments for early diagnosis have been largely achieved through the establishment of the Australian Imaging Biomarker and Lifestyle research group that has followed 1,100 Australians for 11 years. AIBL has also been instrumental in providing insight into the role of the major genetic risk factor apolipoprotein E ϵ4, as well as better understanding the role of lifestyle factors particularly diet, physical activity and sleep to cognitive decline and the accumulation of cerebral Aβ.
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- 2018
31. New Ordinance on Transfer Pricing Documentation Requirements Provides Detailed Guidance on the Implementation of BEPS Action 13 in Germany
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Dawid, R., primary, Ruhmer-Krell, I., additional, Masters, C. (Courtney), additional, and Sommer, C., additional
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- 2017
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32. A Beta
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Masters, C., primary
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- 2017
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33. Reduced TRPC6 mRNA levels in the blood cells of patients with Alzheimer’s disease and mild cognitive impairment
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Lu, R, primary, Wang, J, additional, Tao, R, additional, Zhu, T, additional, Guo, W, additional, Sun, Y, additional, Li, H, additional, Gao, Y, additional, Zhang, W, additional, Fowler, C J, additional, Li, Q, additional, Chen, S, additional, Wu, Z, additional, Masters, C L, additional, Zhong, C, additional, Jing, N, additional, and Wang, Y, additional
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- 2017
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34. PET-only 18F-AV1451 tau quantification
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Bourgeat, P., primary, Villemagne, V. L., additional, Dore, V., additional, Masters, C. L., additional, Ames, D., additional, Rowe, C. C., additional, Salvado, O., additional, and Fripp, J., additional
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- 2017
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35. Imaging of tau deposits in adults with Niemann-Pick type C disease: a case-control study.
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Bozinoski, S., Villemagne, Victor L., Rowe, C. C., Doré, V., Masters, C. L., Walterfang, Mark, and Velakoulis, D.
- Subjects
NIEMANN-Pick diseases ,AMYLOID ,MILD cognitive impairment ,SEVERITY of illness index ,LYSOSOMES - Abstract
Purpose: Niemann-Pick type C (NPC) is a cholesterol storage disease characterized by disruption in the endosomal–lysosomal transport system that leads to the accumulation of cholesterol and glycolipids in lysosomes. Developmental cognitive delay and progressive motor and cognitive impairment are characteristic of the disease. Tau accumulation has been reported in some NPC patients. We investigated the presence of tau and Aβ-amyloid deposits in a group of NPC patients and for comparison in age-matched healthy controls (HC). Methods: Eight NPC patients and seven HC were included in the study. Participants underwent tau imaging with
18 F-AV1451 and amyloid imaging with11 C-PiB. Both18 F-AV1451 and11 C-PiB standardized uptake value ratios were generated using the cerebellar cortex as the reference region. Associations between imaging results, and clinical and neurocognitive parameters were assessed through nonparametric analyses. Results: All participants were Aβ-negative. Four NPC patients presented with high tau burden in the brain. A 21-year-old female patient and a 40-year-old male patient showed high neocortical tau burden in a pattern different from that observed in patients with Alzheimer's disease, while the same 40-year-old male patient, a 40-year-old female patient and a 50-year-old female patient showed high regional tau burden in the mesial temporal cortex. Spearman's correlation analysis showed an association between tau burden in the mesial temporal lobe and age (p = 0.022), and age at symptom onset (p = 0.009), and between frontotemporal tau and duration of symptoms (p = 0.027). There were no correlations between global and regional tau and cognitive parameters. Conclusion: Four of eight NPC patients showed tau deposition in the brain. The results of our exploratory study suggest that while tau deposits do not affect cognitive performance, tau deposits are associated with measures of disease onset and progression. Further studies in a larger cohort of NPC patients are needed to confirm these initial findings. [ABSTRACT FROM AUTHOR]- Published
- 2019
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36. Modulation of retinal arteriolar central reflection by APOE Genotype
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Frost, S., Bhuiyan, A., Offerman, D., Doecke, J.D., Macaulay, S.L., Sohrabi, H.R., Ames, D., Masters, C., Martins, R.N., Kanagasingam, Y., Frost, S., Bhuiyan, A., Offerman, D., Doecke, J.D., Macaulay, S.L., Sohrabi, H.R., Ames, D., Masters, C., Martins, R.N., and Kanagasingam, Y.
- Abstract
Objective: This study investigated the retinal arteriolar central reflex (CR, the central reflection observed in photographs of retinal vessels), which may provide information about micro-vascular health in the retina and also the brain, due to the homology between these vascular networks. The study also describes a novel computer based semi-automated technique that accurately quantifies retinal arteriolar CR and vessel width, and calculates the CR to vessel width ratio (CRR) from digital retinal photographs. Methods: Digital retinal photographs were collected from participants in the Australian Imaging, Biomarkers and Lifestyle study of ageing (AIBL), including 25 participants diagnosed with Alzheimer’s disease (AD) (age 72.4 ± 7.5 yrs, 12 male, 13 female) and 123 elderly participants without dementia (cognitively normals: CN) (age 71.6 ± 5.6 yrs, 55 male, 68 female). Using a sub-cohort of 144 (22 AD, 122 CN) with the novel CRR measures, we identified significantly higher CRR levels in AD participants (mean CRR 0.253 (SD 0.04)) as compared with CN’s (mean CRR 0.231 (SD 0.04), p = 0.025). Adjustment for APOE ε4 allele status however, reduced the significance (p = 0.081). CRR was significantly higher in APOE ε4 allele carriers (mean CRR 0.254 (SD 0.03) as compared with non-carriers (mean CRR 0.224 (SD 0.05), p < 0.0001). Results: These data indicate that CRR is strongly linked to APOE ε4 status and exhibits a weaker, independent trend with AD diagnosis. The retina may be useful as a novel model for non-invasive monitoring of the effects of APOE ε4 on the central nervous system, particularly in cerebrovascular disease.
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- 2017
37. Amyloid ß–associated cognitive decline in the absence of clinical disease progression and systemic illness
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Harrington, K., Lim, Y., Ames, D., Hassenstab, J., Laws, Simon, Martins, R., Rainey-Smith, S., Robertson, J., Rowe, C., Salvado, O., Doré, V., Villemagne, V., Snyder, P., Masters, C., Maruff, P., Harrington, K., Lim, Y., Ames, D., Hassenstab, J., Laws, Simon, Martins, R., Rainey-Smith, S., Robertson, J., Rowe, C., Salvado, O., Doré, V., Villemagne, V., Snyder, P., Masters, C., and Maruff, P.
- Abstract
© 2017 The Authors Introduction High levels of amyloid ß (Aß) are associated with cognitive decline in cognitively normal (CN) older adults. This study investigated the nature of cognitive decline in healthy individuals who did not progress to mild cognitive impairment or dementia. Method Cognition was measured over 72 months and compared between low (Aß-) and high (Aß+) CN older adults (n = 335) who did not progress to mild cognitive impairment or dementia and who remained free of severe or uncontrolled systemic illness. Results Compared to the Aß- group, the Aß+ group showed no cognitive impairment at baseline but showed substantial decline in verbal learning, episodic memory, and attention over 72 months. Discussion Moderate cognitive decline, particularly for learning and memory, was associated with Aß+ in CN older adults in the absence of clinical disease progression and uncontrolled or serious comorbid illness.
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- 2017
38. BDNF Val66Met in preclinical Alzheimer's disease is associated with short-term changes in episodic memory and hippocampal volume but not serum mBDNF
- Author
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Lim, Y., Rainey-Smith, S., Laws, Simon, Gupta, V., Porter, T., Bourgeat, P., Ames, D., Fowler, C., Salvado, O., Villemagne, V., Rowe, C., Masters, C., Zhou, X., Martins, R., Maruff, P., Lim, Y., Rainey-Smith, S., Laws, Simon, Gupta, V., Porter, T., Bourgeat, P., Ames, D., Fowler, C., Salvado, O., Villemagne, V., Rowe, C., Masters, C., Zhou, X., Martins, R., and Maruff, P.
- Abstract
Copyright © International Psychogeriatric Association 2017. Background: The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism Met allele exacerbates amyloid (Aβ) related decline in episodic memory (EM) and hippocampal volume (HV) over 36-54 months in preclinical Alzheimer's disease (AD). However, the extent to which Aβ+ and BDNF Val66Met is related to circulating markers of BDNF (e.g. serum) is unknown. We aimed to determine the effect of Aβ and the BDNF Val66Met polymorphism on levels of serum mBDNF, EM, and HV at baseline and over 18-months. Methods: Non-demented older adults (n = 446) underwent Aβ neuroimaging and BDNF Val66Met genotyping. EM and HV were assessed at baseline and 18 months later. Fasted blood samples were obtained from each participant at baseline and at 18-month follow-up. Aβ PET neuroimaging was used to classify participants as Aβ- or Aβ+. Results: At baseline, Aβ+ adults showed worse EM impairment and lower serum mBDNF levels relative to Aβ- adults. BDNF Val66Met polymorphism did not affect serum mBDNF, EM, or HV at baseline. When considered over 18-months, compared to Aβ- Val homozygotes, Aβ+ Val homozygotes showed significant decline in EM and HV but not serum mBDNF. Similarly, compared to Aβ+ Val homozygotes, Aβ+ Met carriers showed significant decline in EM and HV over 18-months but showed no change in serum mBDNF. Conclusion: While allelic variation in BDNF Val66Met may influence Aβ+ related neurodegeneration and memory loss over the short term, this is not related to serum mBDNF. Longer follow-up intervals may be required to further determine any relationships between serum mBDNF, EM, and HV in preclinical AD.
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- 2017
39. Insulin resistance is associated with reductions in specific cognitive domains and increases in CSF tau in cognitively normal adults
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Laws, S., Gaskin, S., Woodfield, A., Srikanth, V., Bruce, D., Fraser, P., Porter, T., Newsholme, Philip, Wijesekara, N., Burnham, S., Doré, V., Li, Q., Maruff, P., Masters, C., Rainey-Smith, S., Rowe, C., Salvado, O., Villemagne, V., Martins, R., Verdile, Giuseppe, Laws, S., Gaskin, S., Woodfield, A., Srikanth, V., Bruce, D., Fraser, P., Porter, T., Newsholme, Philip, Wijesekara, N., Burnham, S., Doré, V., Li, Q., Maruff, P., Masters, C., Rainey-Smith, S., Rowe, C., Salvado, O., Villemagne, V., Martins, R., and Verdile, Giuseppe
- Abstract
Growing evidence supports the hypothesis that type 2 diabetes (T2D) increases the risk of developing dementia. Experimental evidence from mouse models demonstrates that the induction of T2D/insulin resistance (IR) can promote the accumulation of Alzheimer's disease (AD) pathological features. However, the association of T2D with pathological and clinical phenotypes in humans is unclear. Here we investigate the relationship of indices of IR (HOMA-IR) and pancreatic ß-cell function (HOMA-B) with cognitive performance across several domains (Verbal/Visual Episodic Memory, Executive Function, Language and a measure of Global cognition) and AD biomarkers (CSF Aß42, T-tau/P-tau, hippocampal volume and neocortical Aß-amyloid burden). We reveal that HOMA-IR (p < 0.001) incrementally increases across diagnostic groups, becoming significantly elevated in the AD group compared with cognitively normal (CN) adults. In CN adults, higher HOMA-IR was associated with poorer performance on measures of verbal episodic memory (p = 0.010), executive function (p = 0.046) and global cognition (p = 0.007), as well as with higher CSF T-tau (p = 0.008) and P-tau (p = 0.014) levels. No association was observed with CSF Aß or imaging modalities. Together our data suggest that IR may contribute to reduced cognitive performance and the accumulation of CSF tau biomarkers in cognitively normal adults.
- Published
- 2017
40. Increased Carbohydrate Intake is Associated with Poorer Performance in Verbal Memory and Attention in an APOE Genotype-Dependent Manner
- Author
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Gardener, S., Rainey-Smith, S., Sohrabi, H., Weinborn, M., Verdile, Giuseppe, Fernando, W., Lim, Y., Harrington, K., Burnham, S., Taddei, K., Masters, C., Macaulay, S., Rowe, C., Ames, D., Maruff, P., Martins, R., Gardener, S., Rainey-Smith, S., Sohrabi, H., Weinborn, M., Verdile, Giuseppe, Fernando, W., Lim, Y., Harrington, K., Burnham, S., Taddei, K., Masters, C., Macaulay, S., Rowe, C., Ames, D., Maruff, P., and Martins, R.
- Abstract
Evidence suggests that a diet low in carbohydrates can impact on cognitive performance among those with Alzheimer's disease (AD). However, there is a lack of data assessing this relationship among cognitively normal (CN) older adults at increased future risk of developing AD due to carriage of the apolipoprotein E (APOE) ?4 allele. We assessed the cross-sectional association between carbohydrate intake, cognitive performance, and cerebral amyloid-ß (Aß) load in CN older adults, genotyped for APOE ?4 allele carrier status. Greater carbohydrate intake was associated with poorer performance in verbal memory in APOE ?4 allele non-carriers, and poorer performance in attention in APOE ?4 allele carriers. There were no associations between carbohydrate intake and cerebral Aß load. These results provide support to the idea that decreasing carbohydrate intake may offer neurocognitive benefits, with specific cognitive domains affected in an APOE genotype-dependent manner. These findings warrant further investigation utilizing a longitudinal study design.
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- 2017
41. β-Amyloid, APOE and BDNF genotype, and depressive and anxiety symptoms in cognitively normal older women and men
- Author
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Holmes, Sophie E., Esterlis, Irina, Mazure, Carolyn M., Lim, Yenying, Ames, David J., Rainey-Smith, Stephanie R., Martins, Ralph N., Salvado, Olivier, Doré, Vincent, Villemagne, Victor L., Rowe, Christopher C., Laws, Simon M., Masters, C. L., Maruff, Paul T., Pietrzak, Robert H., Holmes, Sophie E., Esterlis, Irina, Mazure, Carolyn M., Lim, Yenying, Ames, David J., Rainey-Smith, Stephanie R., Martins, Ralph N., Salvado, Olivier, Doré, Vincent, Villemagne, Victor L., Rowe, Christopher C., Laws, Simon M., Masters, C. L., Maruff, Paul T., and Pietrzak, Robert H.
- Abstract
Objective To examine how β-amyloid (Aβ), APOE and BDNF genotypes, and cortisol relate to depressive and anxiety symptoms in cognitively normal older women and men. Methods Cross-sectional data were analyzed from 423 older adults from the Australian Imaging Biomarkers and Lifestyle study. Analyses of covariance evaluated associations between Aβ, APOE and BDNF genotype, and cortisol in relation to severity of depressive and anxiety symptoms. Results Among Aβ+ older adults, APOE ε4 carriage was associated with greater severity of anxiety symptoms (d = 0.55); and in the full sample, APOE ε4 carriage was linked to greater severity of depressive (d = 0.26) and anxiety (d = 0.21) symptoms. Among Aβ+ women, ε4 carriers reported greater anxiety symptoms than non-ε4 carriers (d = 0.83), and female BDNF rs6265 Val66 Met allele carriers reported greater depressive symptoms (d = 0.29). Conclusion Sex moderated the relationship between Aβ, APOE genotype, and BDNF genotype in predicting severity of anxiety and depressive symptoms in cognitively normal older adults. © 2016 American Association for Geriatric Psychiatry
- Published
- 2016
42. Corrigendum to ‘Self and informant memory concerns align in healthy memory complainers and in early stages of mild cognitive impairment but separate with increasing cognitive impairment’
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Buckley, R., Saling, M., Ellis, K., Rowe, C., Maruff, P., Macaulay, L.S., Martins, R., Masters, C., Savage, G., Rainey-Smith, S., Rembach, A., Ames, D., Buckley, R., Saling, M., Ellis, K., Rowe, C., Maruff, P., Macaulay, L.S., Martins, R., Masters, C., Savage, G., Rainey-Smith, S., Rembach, A., and Ames, D.
- Abstract
This is a correction to: Age and Ageing, Volume 44, Issue 6, November 2015, Pages 1012–1019, https://doi.org/10.1093/ageing/afv136
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- 2016
43. Plasma phospholipid and sphingolipid alterations in presenilin1 mutation carriers: A pilot study
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Chatterjee, P., Lim, W.L.F., Shui, G., Gupta, V.B., James, I., Fagan, A.M., Xiong, C., Sohrabi, H.R., Taddei, K., Brown, B.M., Benzinger, T., Masters, C., Snowden, S.G., Wenk, M.R., Bateman, R.J., Morris, J.C., Martins, R.N., Chatterjee, P., Lim, W.L.F., Shui, G., Gupta, V.B., James, I., Fagan, A.M., Xiong, C., Sohrabi, H.R., Taddei, K., Brown, B.M., Benzinger, T., Masters, C., Snowden, S.G., Wenk, M.R., Bateman, R.J., Morris, J.C., and Martins, R.N.
- Abstract
Background and Objective: Aberrant lipid metabolism has been implicated in sporadic Alzheimer’s disease (AD). The current study investigated plasma phospholipid and sphingolipid profiles in individuals carrying PSEN1 mutations responsible for autosomal dominant AD (ADAD). Methods: Study participants evaluated were from the Perth and Melbourne sites of the Dominantly Inherited Alzheimer Network (DIAN) study. Plasma phospholipid and sphingolipid profiles were measured using liquid chromatography coupled with mass spectrometry in 20 PSEN1 mutation carriers (MC; eight of whom were symptomatic and twelve asymptomatic, based on Clinical Dementia Rating scores) and compared with six non carriers (NC) using linear mixed models. Further, AD gold standard biomarker data obtained from the DIAN database were correlated with lipid species significantly altered between MC and NC, using Spearman’s correlation coefficient. Results: One-hundred and thirty-nine plasma phospholipid and sphingolipid species were measured. Significantly altered species in MC compared to NC primarily belonged to choline and ethanolamine containing phospholipid classes and ceramides. Further phosphatidylcholine species (34:6, 36:5, 40:6) correlated with cerebrospinal fluid tau (p < 0.05), and plasmalogen ethanolamine species (34:2, 36:,4) correlated with both cerebrospinal fluid tau and brain amyloid load within the MC group (p < 0.05). Conclusion: These findings indicate altered phospholipid and sphingolipid metabolism in ADAD and provide insight into the pathomolecular changes occurring with ADAD pathogenesis. Further, findings reported in this study allow comparison of lipid alterations in ADAD with those reported previously in sporadic AD. The findings observed in the current pilot study warrant validation in the larger DIAN cohort.
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- 2016
44. ß-Amyloid, APOE and BDNF Genotype, and Depressive and Anxiety Symptoms in Cognitively Normal Older Women and Men
- Author
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Holmes, S., Esterlis, I., Mazure, C., Lim, Y., Ames, D., Rainey-Smith, S., Martins, R., Salvado, O., Dore, V., Villemagne, V., Rowe, C., Laws, Simon, Masters, C., Maruff, P., Pietrzak, R., Holmes, S., Esterlis, I., Mazure, C., Lim, Y., Ames, D., Rainey-Smith, S., Martins, R., Salvado, O., Dore, V., Villemagne, V., Rowe, C., Laws, Simon, Masters, C., Maruff, P., and Pietrzak, R.
- Abstract
© 2016 American Association for Geriatric PsychiatryObjective To examine how ß-amyloid (Aß), APOE and BDNF genotypes, and cortisol relate to depressive and anxiety symptoms in cognitively normal older women and men. Methods Cross-sectional data were analyzed from 423 older adults from the Australian Imaging Biomarkers and Lifestyle study. Analyses of covariance evaluated associations between Aß, APOE and BDNF genotype, and cortisol in relation to severity of depressive and anxiety symptoms. Results Among Aß+ older adults, APOE e4 carriage was associated with greater severity of anxiety symptoms (d?=?0.55); and in the full sample, APOE e4 carriage was linked to greater severity of depressive (d?=?0.26) and anxiety (d?=?0.21) symptoms. Among Aß+ women, e4 carriers reported greater anxiety symptoms than non-e4 carriers (d?=?0.83), and female BDNF rs6265 Val66 Met allele carriers reported greater depressive symptoms (d?=?0.29). Conclusion Sex moderated the relationship between Aß, APOE genotype, and BDNF genotype in predicting severity of anxiety and depressive symptoms in cognitively normal older adults.
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- 2016
45. Impact of Mild Head Injury on Neuropsychological Performance in Healthy Older Adults: Longitudinal Assessment in the AIBL Cohort
- Author
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Albrecht, Matthew, Masters, C., Ames, D., Foster, J., Albrecht, Matthew, Masters, C., Ames, D., and Foster, J.
- Abstract
Traumatic brain injury (TBI) is suggested to be a significant risk factor for dementia. However, little research has been conducted into long-term neuropsychological outcomes after head trauma. Participants from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing (AIBL) who had recovered after sustaining a mild TBI involving loss of consciousness more than 5 years previously were compared with matched controls across a 3-year period. Bayesian nested-domain modeling was used to estimate the effect of TBI on neuropsychological performance. There was no evidence for a chronic effect of mild TBI on any neuropsychological domain compared to controls. Within the TBI group, there was some evidence suggesting that the age that the head trauma occurred and the duration of unconsciousness were modulators of episodic memory. However, these findings were not robust. Taken together, these findings indicate that adults who have sustained a TBI resulting in loss of consciousness, but who recover to a healthy level of cognitive functioning, do not experience frank deficits in cognitive ability.
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- 2016
46. Clinical and cognitive trajectories in cognitively healthy elderly individuals with suspected non-Alzheimer's disease pathophysiology (SNAP) or Alzheimer's disease pathology: a longitudinal study.
- Author
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Burnham, S., Bourgeat, P., Dore, V., Savage, G., Brown, B., Laws, Simon, Maruff, P., Salvado, O., Ames, D., Martins, R., Masters, C., Rowe, C., Villemagne, V., Burnham, S., Bourgeat, P., Dore, V., Savage, G., Brown, B., Laws, Simon, Maruff, P., Salvado, O., Ames, D., Martins, R., Masters, C., Rowe, C., and Villemagne, V.
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- 2016
47. Longitudinal cognitive decline in the AIBL cohort: The role of APOE e4 status
- Author
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Albrecht, Matthew, Szoeke, C., Maruff, P., Savage, G., Lautenschlager, N., Ellis, K., Taddei, K., Martins, R., Masters, C., Ames, D., Foster, Jonathan, Albrecht, Matthew, Szoeke, C., Maruff, P., Savage, G., Lautenschlager, N., Ellis, K., Taddei, K., Martins, R., Masters, C., Ames, D., and Foster, Jonathan
- Abstract
The ε4 polymorphism of the APOE gene confers a substantially increased risk of developing Alzheimer's disease. However, the influence of the ε4 allele on age-related cognitive functioning is more contentious. Previously, we demonstrated relatively little evidence for a role of the ε4 allele on baseline cognitive performance in older adults in the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing (Foster et al., 2013). We here investigated whether the APOE ε4 allele influenced cognitive status over time when the AIBL cohort was studied longitudinally over a 3-year period. The AIBL neuropsychological test battery was administered at baseline, after 18 months and again after 36 months. Participants comprised 764 Healthy Controls and 131 Mild Cognitively Impaired individuals enroled in the AIBL Study of Ageing. We compared individuals within each group with and without an ε4 allele. Healthy Controls with an ε4 allele manifested a modest acceleration in cognitive decline over 36 months on measures of verbal episodic memory. By contrast, Mild Cognitively Impaired individuals with an ε4 allele showed increased cognitive decline across a range of cognitive tasks, putatively reflecting early cognitive signs of Alzheimer's disease. Given the long prodromal period that has been noted in late onset Alzheimer's disease, we suggest that these findings are consistent with a prodromal account rather than a phenotypic account of ε4-related cognitive ageing.
- Published
- 2015
48. APOE ε4 Moderates Amyloid-related Memory Decline In Preclinical Alzheimer's Disease
- Author
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Lim, Yenying, Villemagne, Victor L., Pietrzak, Robert H., Ames, David J., Ellis, K. A., Harrington, Karra D., Snyder, Peter J., Martins, Ralph, Masters, C. L., Rowe, Christopher C., Maruff, P., Lim, Yenying, Villemagne, Victor L., Pietrzak, Robert H., Ames, David J., Ellis, K. A., Harrington, Karra D., Snyder, Peter J., Martins, Ralph, Masters, C. L., Rowe, Christopher C., and Maruff, P.
- Abstract
The apolipoprotein E (APOE) e{open}4 allele and high levels of beta-amyloid (Aβ) are associated with episodic memory decline and risk for Alzheimer's disease. However, there is debate about independent or interactive effects of e{open}4 on Aβ-related memory decline in healthy older adults. Healthy older adults with high Aβ burden (n= 84) enrolled in Australian Imaging, Biomarkers, and Lifestyle Study were included in this study. Cognition was measured using the computerized Cogstate Brief Battery at baseline, 18-, 36-, and 54-month follow-ups. Mini Mental State Examination and Clinical Dementia Rating scales were also administered at baseline and each follow-up timepoint. Relative to Aβ+ e{open}4 noncarriers (n= 36), Aβ+ e{open}4 carriers (n= 48) showed significantly faster decline on memory tasks, which was by convention, moderate in magnitude (d= 0.40-0.47). Aβ positivity coupled with APOE e{open}4 was associated with moderately increased decline in memory over a 54-month assessment period, suggesting that, in the preclinical stages of Alzheimer's disease, the manifestation of memory decline in older adults with high Aβ is exacerbated by the presence of APOE e{open}4.
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- 2015
49. Alzheimer's Disease Normative Cerebrospinal Fluid Biomarkers Validated In Pet Amyloid-β Characterized Subjects From The Australian Imaging, Biomarkers And Lifestyle (AIBL) Study
- Author
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Li, Qiaoxin, Villemagne, Victor L., Doecke, James D., Rembach, Alan R., Sarros, Shannon, Varghese, Shiji, McGlade, Amelia R., Laughton, Katrina M., Pertile, Kelly K., Fowler, Christopher J., Rumble, Rebecca L., Trounson, Brett O., Taddei, Kevin, Rainey-Smith, Stephanie, Laws, Simon, Robertson, Joanne S., Evered, Lisbeth A., Silbert, Brendan S., Ellis, K. A., Rowe, Christopher C., Macaulay, Stuart L., Darby, David G., Martins, Ralph, Ames, David, Masters, C. L., Collins, Steven J., Li, Qiaoxin, Villemagne, Victor L., Doecke, James D., Rembach, Alan R., Sarros, Shannon, Varghese, Shiji, McGlade, Amelia R., Laughton, Katrina M., Pertile, Kelly K., Fowler, Christopher J., Rumble, Rebecca L., Trounson, Brett O., Taddei, Kevin, Rainey-Smith, Stephanie, Laws, Simon, Robertson, Joanne S., Evered, Lisbeth A., Silbert, Brendan S., Ellis, K. A., Rowe, Christopher C., Macaulay, Stuart L., Darby, David G., Martins, Ralph, Ames, David, Masters, C. L., and Collins, Steven J.
- Abstract
Background: The cerebrospinal fluid (CSF) amyloid-β (Aβ)1-42, total-tau (T-tau), and phosphorylated-tau (P-tau181P) profile has been established as a valuable biomarker for Alzheimer's disease (AD). Objective: The current study aimed to determine CSF biomarker cut-points using positron emission tomography (PET) Aβ imaging screened subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, as well as correlate CSF analyte cut-points across a range of PET Aβ amyloid ligands. Methods: Aβ pathology was determined by PET imaging, utilizing 11C-Pittsburgh Compound B, 18F-flutemetamol, or 18Fflorbetapir, in 157 AIBL participants who also underwent CSF collection. Using anINNOTEST assay, cut-points were established (Aβ 1-42 >544 ng/L, T-tau/L, and P-tau181P/L) employing a rank based method to define a positive CSF in the sub-cohort of amyloid-PET negative healthy participants (n = 97), and compared with the presence of PET demonstrated AD pathology. Results: CSF Aβ 1-42 was the strongest individual biomarker, detecting cognitively impaired PET positive mild cognitive impairment (MCI)/AD with 85% sensitivity and 91% specificity. The ratio of P-tau181P or T-tau to Aβ1-42 provided greater accuracy, predicting MCI/AD with Aβ pathology with ?92% sensitivity and specificity. Cross-validated accuracy, using all three biomarkers or the ratio of P-tau or T-tau to Aβ 1-42 to predict MCI/AD, reached ?92% sensitivity and specificity. Conclusions: CSF Aβ1-42 levels and analyte combination ratios demonstrated very high correlation with PET Aβ imaging. Our study offers additional support for CSF biomarkers in the early and accurate detection of AD pathology, including enrichment of patient cohorts for treatment trials even at the pre-symptomatic stage.
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- 2015
50. Novel Statistically-Derived Composite Measures for Assessing The Efficacy of Disease-Modifying Therapies In Prodromal Alzheimer's Disease Trials: An AIBL Study
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Burnham, Samantha C., Raghavan, Nandini, Wilson, William, Baker, David, Ropacki, Michael T., Novak, Gerald P., Ames, David J., Ellis, K. A., Martins, Ralph, Maruff, P., Masters, C. L., Romano, Gary, Rowe, Christopher c., Savage, Greg R., Macaulay, Stuart L., Narayan, Vaibhav A., Burnham, Samantha C., Raghavan, Nandini, Wilson, William, Baker, David, Ropacki, Michael T., Novak, Gerald P., Ames, David J., Ellis, K. A., Martins, Ralph, Maruff, P., Masters, C. L., Romano, Gary, Rowe, Christopher c., Savage, Greg R., Macaulay, Stuart L., and Narayan, Vaibhav A.
- Abstract
Background: There is a growing consensus that disease-modifying therapies must be given at the prodromal or preclinical stages of Alzheimer's disease (AD) to be effective. A major unmet need is to develop and validate sensitive measures to track disease progression in these populations. Objective: To generate novel statistically-derived composites from standard scores, which have increased sensitivity in the assessment of change from baseline in prodromal AD. Methods: An empirically based method was employed to generate domain specific, global, and cognitive-functional novel composites. The novel composites were compared and contrasted with each other, as well as standard scores for their ability to track change from baseline. The longitudinal characteristics and power to detect decline of the measures were evaluated. Data from participants in the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study characterized as mild cognitively impaired with high neocortical amyloid-β burden were utilized for the study. Results: The best performing standard scores were CDR Sum-of-Boxes and MMSE. The statistically-derived novel composites performed better than the standard scores from which they were derived. The domain-specific composites generally did not perform as well as the global composites or the cognitive-functional composites. Conclusion: A systematic method was employed to generate novel statistically-derived composite measures from standard scores. Composites comprised of measures including function and multiple cognitive domains appeared to best capture change from baseline. These composites may be useful to assess progression or lack thereof in prodromal AD. However, the results should be replicated and validated using an independent clinical sample before implementation in a clinical trial.
- Published
- 2015
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