Journal ArticleDOI
Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study.
Victor L. Villemagne,Samantha C. Burnham,Pierrick Bourgeat,Belinda M. Brown,Kathryn A. Ellis,Olivier Salvado,Cassandra Szoeke,S. Lance Macaulay,Ralph N. Martins,Paul Maruff,David Ames,Christopher C. Rowe,Colin L. Masters +12 more
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TLDR
These projections suggest a prolonged preclinical phase of AD in which Aβ deposition reaches the authors' threshold of positivity at 17·0 (95% CI 14·9-19·9) years, hippocampal atrophy at 4·2 (3·6-5·1] years, and memory impairment at 3·3 (2·5-4·5) years before the onset of dementia (clinical dementia rating score 1).Abstract:
Summary Background Similar to most chronic diseases, Alzheimer's disease (AD) develops slowly from a preclinical phase into a fully expressed clinical syndrome. We aimed to use longitudinal data to calculate the rates of amyloid β (Aβ) deposition, cerebral atrophy, and cognitive decline. Methods In this prospective cohort study, healthy controls, patients with mild cognitive impairment (MCI), and patients with AD were assessed at enrolment and every 18 months. At every visit, participants underwent neuropsychological examination, MRI, and a carbon-11-labelled Pittsburgh compound B ( 11 C-PiB) PET scan. We included participants with three or more 11 C-PiB PET follow-up assessments. Aβ burden was expressed as 11 C-PiB standardised uptake value ratio (SUVR) with the cerebellar cortex as reference region. An SUVR of 1·5 was used to discriminate high from low Aβ burdens. The slope of the regression plots over 3–5 years was used to estimate rates of change for Aβ deposition, MRI volumetrics, and cognition. We included those participants with a positive rate of Aβ deposition to calculate the trajectory of each variable over time. Findings 200 participants (145 healthy controls, 36 participants with MCI, and 19 participants with AD) were assessed at enrolment and every 18 months for a mean follow-up of 3·8 (95% CI CI 3·6–3·9) years. At baseline, significantly higher Aβ burdens were noted in patients with AD (2·27, SD 0·43) and those with MCI (1·94, 0·64) than in healthy controls (1·38, 0·39). At follow-up, 163 (82%) of the 200 participants showed positive rates of Aβ accumulation. Aβ deposition was estimated to take 19·2 (95% CI 16·8–22·5) years in an almost linear fashion—with a mean increase of 0·043 (95% CI 0·037–0·049) SUVR per year—to go from the threshold of 11 C-PiB positivity (1·5 SUVR) to the levels observed in AD. It was estimated to take 12·0 (95% CI 10·1–14·9) years from the levels observed in healthy controls with low Aβ deposition (1·2 [SD 0·1] SUVR) to the threshold of 11 C-PiB positivity. As AD progressed, the rate of Aβ deposition slowed towards a plateau. Our projections suggest a prolonged preclinical phase of AD in which Aβ deposition reaches our threshold of positivity at 17·0 (95% CI 14·9–19·9) years, hippocampal atrophy at 4·2 (3·6–5·1) years, and memory impairment at 3·3 (2·5–4·5) years before the onset of dementia (clinical dementia rating score 1). Interpretation Aβ deposition is slow and protracted, likely to extend for more than two decades. Such predictions of the rate of preclinical changes and the onset of the clinical phase of AD will facilitate the design and timing of therapeutic interventions aimed at modifying the course of this illness. Funding Science and Industry Endowment Fund (Australia), The Commonwealth Scientific and Industrial Research Organisation (Australia), The National Health and Medical Research Council of Australia Program and Project Grants, the Austin Hospital Medical Research Foundation, Victorian State Government, The Alzheimer's Drug Discovery Foundation, and the Alzheimer's Association.read more
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Journal ArticleDOI
Curcumin and cognition: a randomised, placebo-controlled, double-blind study of community-dwelling older adults.
Stephanie R. Rainey-Smith,Belinda M. Brown,Hamid R. Sohrabi,Tejal M. Shah,Kathryn Goozee,Veer Bala Gupta,Ralph N. Martins +6 more
TL;DR: The findings of this 12-month, randomised, placebo-controlled, double-blind study that investigated the ability of a curcumin formulation to prevent cognitive decline in a population of community-dwelling older adults suggest that further longitudinal assessment is required to investigate changes in cognitive outcome measures.
Journal ArticleDOI
Polygenic risk of Alzheimer disease is associated with early- and late-life processes
Elizabeth C. Mormino,Reisa A. Sperling,Avram J. Holmes,Randy L. Buckner,Philip L. De Jager,Jordan W. Smoller,Mert R. Sabuncu +6 more
TL;DR: Effects related to common genetic risk loci distributed throughout the genome are detectable among individuals without dementia, and the influence of this genetic risk may begin in early life and make an individual more susceptible to cognitive impairment in late life.
Journal ArticleDOI
Plasma amyloid β 42/40 ratios as biomarkers for amyloid β cerebral deposition in cognitively normal individuals
Noelia Fandos,Virginia Pérez-Grijalba,Pedro Pesini,Salvador Olmos,Matias Bossa,Victor L. Villemagne,James D. Doecke,Christopher Fowler,Colin L. Masters,Manuel Sarasa +9 more
TL;DR: Plasma amyloid β (Aβ) peptides have been previously studied as candidate biomarkers to increase recruitment efficiency in secondary prevention clinical trials for Alzheimer's disease.
Journal ArticleDOI
Gantenerumab reduces amyloid-β plaques in patients with prodromal to moderate Alzheimer's disease: a PET substudy interim analysis.
Gregory Klein,Paul Delmar,Nicola Voyle,Sunita Rehal,Carsten Hofmann,Danielle Abi-Saab,Mirjana Andjelkovic,Smiljana Ristic,Guoqiao Wang,Randall J. Bateman,Geoffrey A. Kerchner,Monika Baudler,Paulo Fontoura,Rachelle Doody +13 more
TL;DR: Results from this exploratory interim analysis of the PET substudy suggest that gantenerumab doses up to 1200 mg resulted in robust amyloid-β plaque removal at 2 years, similar to other placebo-controlled studies that have suggested potential clinical benefit.
Journal ArticleDOI
APOE and BDNF polymorphisms moderate amyloid β-related cognitive decline in preclinical Alzheimer’s disease
Yen Ying Lim,Yen Ying Lim,Yen Ying Lim,Victor L. Villemagne,Victor L. Villemagne,Simon M. Laws,Simon M. Laws,Simon M. Laws,R. H. Pietrzak,Peter J. Snyder,Peter J. Snyder,David Ames,Kathryn A. Ellis,Karra Harrington,Alan Rembach,Ralph N. Martins,Christopher C. Rowe,Colin L. Masters,Paul Maruff +18 more
TL;DR: At least two genetic loci affect the rate of Aβ-related cognitive decline, and Aβ+ɛ4+/BDNFMet individuals can expect to show clinically significant memory impairment after 3 years, whereas A β+ɚ4+ /BDNFVal/Val individuals can Expect a similar degree of impairment after 10 years.
References
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Journal ArticleDOI
Clinical diagnosis of Alzheimer's disease : report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease
Guy M. McKhann,David A. Drachman,Marshall F. Folstein,Robert Katzman,Donald L. Price,Emanuel M. Stadlan +5 more
TL;DR: The criteria proposed are intended to serve as a guide for the diagnosis of probable, possible, and definite Alzheimer's disease; these criteria will be revised as more definitive information becomes available.
Proceedings Article
Information Theory and an Extention of the Maximum Likelihood Principle
TL;DR: The classical maximum likelihood principle can be considered to be a method of asymptotic realization of an optimum estimate with respect to a very general information theoretic criterion to provide answers to many practical problems of statistical model fitting.
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Information Theory and an Extension of the Maximum Likelihood Principle
TL;DR: In this paper, it is shown that the classical maximum likelihood principle can be considered to be a method of asymptotic realization of an optimum estimate with respect to a very general information theoretic criterion.
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The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's disease
Guy M. McKhann,Guy M. McKhann,David S. Knopman,Howard Chertkow,Bradley T. Hyman,Clifford R. Jack,Claudia H. Kawas,William E. Klunk,Walter J. Koroshetz,Jennifer J. Manly,Richard Mayeux,Richard C. Mohs,John C. Morris,Martin N. Rossor,Philip Scheltens,Maria C. Carrillo,Bill Thies,Sandra Weintraub,Creighton H. Phelps +18 more
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Mild Cognitive Impairment: Clinical Characterization and Outcome
Ronald C. Petersen,Glenn E. Smith,Stephen C. Waring,Robert J. Ivnik,Eric G. Tangalos,Emre Kokmen +5 more
TL;DR: Patients who meet the criteria for MCI can be differentiated from healthy control subjects and those with very mild AD, and appear to constitute a clinical entity that can be characterized for treatment interventions.
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