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
Magnetic resonance imaging in Alzheimer's Disease Neuroimaging Initiative 2
Clifford R. Jack,Josephine Barnes,Matt A. Bernstein,Bret J. Borowski,James B. Brewer,Shona Clegg,Anders M. Dale,Owen Carmichael,Christopher R.K. Ching,Charles DeCarli,Rahul S. Desikan,Christine Fennema-Notestine,Anders M. Fjell,Evan Fletcher,Nick C. Fox,Jeff Gunter,Boris A. Gutman,Dominic Holland,Xue Hua,Philip S. Insel,Kejal Kantarci,Ronald J. Killiany,Gunnar Krueger,Kelvin K. Leung,Scott Mackin,Scott Mackin,Pauline Maillard,Ian B. Malone,Niklas Mattsson,Linda K. McEvoy,Marc Modat,Susanne G. Mueller,Susanne G. Mueller,Rachel L. Nosheny,Rachel L. Nosheny,Sebastien Ourselin,Norbert Schuff,Norbert Schuff,Matthew L. Senjem,Alix Simonson,Paul M. Thompson,Dan Rettmann,Prashanthi Vemuri,Kristine B. Walhovd,Yansong Zhao,Samantha M. Zuk,Michael W. Weiner +46 more
TL;DR: The primary objective of the magnetic resonance imaging (MRI) core of ADNI has been to improve methods for clinical trials in Alzheimer's disease and related disorders.
Journal ArticleDOI
Associations Between Biomarkers and Age in the Presenilin 1 E280A Autosomal Dominant Alzheimer Disease Kindred: A Cross-sectional Study
Adam S. Fleisher,Kewei Chen,Yakeel T. Quiroz,Yakeel T. Quiroz,Laura Jakimovich,Madelyn Gutierrez Gomez,Carolyn M. Langois,Jessica B. Langbaum,Auttawut Roontiva,Pradeep Thiyyagura,Wendy Lee,Napatkamon Ayutyanont,Liliana Lopez,Sonia Moreno,Claudia Muñoz,Victoria Tirado,Natalia Acosta-Baena,Anne M. Fagan,Margarita Giraldo,Gloria María Gallego García,Matthew J. Huentelman,Pierre N. Tariot,Francisco Lopera,Eric M. Reiman +23 more
TL;DR: Compared with noncarriers, cognitively unimpaired mutation carriers had significantly lower precuneus cerebral metabolic rates for glucose, smaller hippocampal volume, lower CSF Aβ1-42, higher CSF total tau and phosphorylated tau181, and higher plasma Aβ 1-42 measurements.
Journal ArticleDOI
The Link between Type 2 Diabetes and Neurodegeneration: Roles for Amyloid-β, Amylin, and Tau Proteins
Prashant Bharadwaj,Prashant Bharadwaj,Nadeeja Wijesekara,Milindu Liyanapathirana,Philip Newsholme,Lars M. Ittner,Paul E. Fraser,Giuseppe Verdile,Giuseppe Verdile,Giuseppe Verdile +9 more
TL;DR: Evidence indicating T2D in promoting Aβ and tau mediated neurodegeneration and the potential contributions of Aβand tau in promoting a diabetic phenotype that could further exacerbate neurodegenersation are highlighted.
Journal ArticleDOI
Nanotechnology-based drug delivery systems for Alzheimer's disease management: Technical, industrial, and clinical challenges.
Ming Ming Wen,Noha S. El-Salamouni,Wessam M. El-Refaie,Heba A. Hazzah,Mai M. Ali,Giovanni Tosi,Ragwa M. Farid,María J. Blanco-Prieto,Nashiru Billa,Amira Sayed Hanafy +9 more
TL;DR: A review of the recent studies conducted on NTDDS for AD treatment, with a primary focus on the industrial perspectives and processability, highlights the ongoing clinical trials for AD management.
Journal ArticleDOI
The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics
Eric Karran,Bart De Strooper +1 more
TL;DR: In this article , the temporal interplay between the two pathognomonic protein aggregates in AD and their relationship to cognitive impairment was investigated. And the authors concluded that the speed of amyloid removal from the brain by a potential therapy will be important in demonstrating clinical benefit in the context of clinical trial.
References
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