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
Evaluation of Cholinergic Deficiency in Preclinical Alzheimer's Disease Using Pupillometry
Shaun Frost,Liam Robinson,Christopher C. Rowe,David Ames,Colin L. Masters,Kevin Taddei,Stephanie R. Rainey-Smith,Stephanie R. Rainey-Smith,Ralph N. Martins,Yogesan Kanagasingam +9 more
TL;DR: The results suggest that PFR changes may occur in the preclinical phase of AD, suggesting pupillometry has a potential as an adjunct for noninvasive, cost-effective screening for preclinical AD.
Journal ArticleDOI
Safety, tolerability and efficacy of the glutaminyl cyclase inhibitor PQ912 in Alzheimer's disease: results of a randomized, double-blind, placebo-controlled phase 2a study.
Philip Scheltens,Merja Hallikainen,Timo Grimmer,Thomas Duning,Alida A. Gouw,Charlotte E. Teunissen,Alle Meije Wink,Paul Maruff,John Harrison,John Harrison,Caroline M van Baal,Suzanne Bruins,Inge Lues,Niels D. Prins +13 more
TL;DR: The maximal tolerated dose of PQ912 has been identified and the results support future studies at still lower doses reaching > 50% target occupancy, a longer up-titration phase to potentially induce adaptation and longer treatment periods to confirm the early signals of efficacy as seen in this study.
Journal ArticleDOI
Passive immunotherapies targeting Aβ and tau in Alzheimer's disease.
TL;DR: The molecular-level strategies that researchers are using to design an effective therapeutic antibody, given the challenges in treating Alzheimer's disease are discussed.
Journal ArticleDOI
The role of 5 HT6-receptor antagonists in Alzheimer's disease: an update.
TL;DR: Findings of preclinical and phase I–III clinical trials conducted with three major 5-HT6 receptor antagonists in the field of AD are discussed, finding that Investigating 5- HT6 receptor partial or inverse agonists may be promising in future AD trials.
Journal ArticleDOI
An inflammatory and trophic disconnect biomarker profile revealed in Down syndrome plasma: Relation to cognitive decline and longitudinal evaluation
M. Florencia Iulita,Alison Ower,Concetta Barone,Rowan Pentz,Palma Gubert,Corrado Romano,Rita Anna Cantarella,Flaviana Elia,Serafino Buono,Marilena Recupero,Carmelo Romano,Sabrina Castellano,Paolo Bosco,Santo Di Nuovo,Filippo Drago,Filippo Caraci,A. Claudio Cuello +16 more
TL;DR: Given that Alzheimer's pathology develops silently over decades in Down syndrome (DS), prognostic biomarkers of dementia are a major need.
References
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Journal ArticleDOI
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Guy M. McKhann,David A. Drachman,Marshall F. Folstein,Robert Katzman,Donald L. Price,Emanuel M. Stadlan +5 more
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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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Ronald C. Petersen,Glenn E. Smith,Stephen C. Waring,Robert J. Ivnik,Eric G. Tangalos,Emre Kokmen +5 more
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