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
Transcriptional signature in microglia associated with Aβ plaque phagocytosis.
Alexandra Grubman,Alexandra Grubman,Alexandra Grubman,Xin Yi Choo,Gabriel Chew,John F. Ouyang,Guizhi Sun,Guizhi Sun,Guizhi Sun,Nathan P. Croft,Fernando J. Rossello,Fernando J. Rossello,Fernando J. Rossello,Rebecca K. Simmons,Rebecca K. Simmons,Sam Buckberry,Sam Buckberry,Dulce Vargas Landin,Dulce Vargas Landin,Jahnvi Pflueger,Jahnvi Pflueger,Teresa H. Vandekolk,Zehra C. Abay,Zehra C. Abay,Zehra C. Abay,Yichen Zhou,Xiaodong Liu,Xiaodong Liu,Xiaodong Liu,Joseph Chen,Joseph Chen,Joseph Chen,Michael R. Larcombe,Michael R. Larcombe,Michael R. Larcombe,John M. Haynes,Catriona McLean,Sarah M. Williams,Sarah M. Williams,Sarah M. Williams,Siew Yeen Chai,Trevor J Wilson,Ryan Lister,Ryan Lister,Colin W. Pouton,Anthony W. Purcell,Owen J. L. Rackham,Enrico Petretto,Jose M. Polo,Jose M. Polo,Jose M. Polo +50 more
TL;DR: The role of microglia cells in Alzheimer's disease (AD) is well recognized, however their molecular and functional diversity remain unclear as mentioned in this paper, however their role in AD is not well understood.
Journal ArticleDOI
A review of β-amyloid neuroimaging in Alzheimer's disease.
Paul A. Adlard,Bob A Tran,David Finkelstein,Patricia Desmond,Patricia Desmond,Leigh A. Johnston,Leigh A. Johnston,Ashley I. Bush,Gary F. Egan +8 more
TL;DR: The main efforts of neuroimaging in AD in humans and in mouse models are summarized, with a specific focus on β-amyloid, and the potential of new applications and novel approaches are discussed.
Journal ArticleDOI
Genetic variants in Alzheimer disease – molecular and brain network approaches
TL;DR: How the study of molecular, cellular and brain networks provides additional information on the effects of LOAD-associated genetic variants at multiple biophysical scales is discussed and the clinical potential of mechanistically coupling genetic variants and disease phenotypes with multiscale brain models is highlighted.
Journal ArticleDOI
Microglial activation and tau burden predict cognitive decline in Alzheimer's disease.
Maura Malpetti,Rogier A. Kievit,Luca Passamonti,Luca Passamonti,P. Simon Jones,Kamen A. Tsvetanov,Timothy Rittman,Elijah Mak,Nicolas Nicastro,Nicolas Nicastro,W Richard Bevan-Jones,Li Su,Young T. Hong,Tim D. Fryer,Franklin I. Aigbirhio,John T. O'Brien,James B. Rowe,James B. Rowe +17 more
TL;DR: Higher temporoparietal tau burden and neuroinflammation at baseline predict faster cognitive decline over 3 years, and are more prognostic than baseline MRI measures of atrophy.
Journal ArticleDOI
PET staging of amyloidosis using striatum
Bernard Hanseeuw,Bernard Hanseeuw,Rebecca A. Betensky,Elizabeth C. Mormino,Aaron P. Schultz,Jorge Sepulcre,John A. Becker,Heidi I.L. Jacobs,Heidi I.L. Jacobs,Rachel F. Buckley,Molly R. LaPoint,Patrizia Vannini,Patrizia Vannini,Nancy J. Donovan,Nancy J. Donovan,Jasmeer P. Chhatwal,Gad A. Marshall,Gad A. Marshall,Kathryn V. Papp,Kathryn V. Papp,Rebecca E. Amariglio,Rebecca E. Amariglio,Dorene M. Rentz,Dorene M. Rentz,Reisa A. Sperling,Reisa A. Sperling,Keith A. Johnson,Keith A. Johnson +27 more
TL;DR: A three‐stage PET classification is evaluated: low cortical; high cortical, low striatal; and high cortex, high striatal amyloid; hypothesizing this model could better reflect Alzheimer's dementia progression than a model based only on cortical measures.
References
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