Regional dynamics of amyloid-β deposition in healthy elderly, mild cognitive impairment and Alzheimer’s disease: a voxelwise PiB–PET longitudinal study
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Amyloid-β deposition in Alzheimer's disease is thought to start while individuals are still cognitively unimpaired and it is hypothesized that after an early phase of fast accumulation, a plateau is reached by the time of cognitive decline. However, few longitudinal Pittsburgh compound B-positron emission tomography studies have tested this hypothesis, and with conflicting results. The purpose of this work is to further our understanding of the dynamics of amyloid-β deposition in a large longitudinal cohort. A total of 32 patients with Alzheimer's disease, 49 subjects with mild cognitive impairment and 103 healthy controls underwent two Pittsburgh compound B-positron emission tomography scans 18 months apart. For each participant, a parametric map of Pittsburgh compound B-positron emission tomography rate of change was created [(follow-up scan - baseline scan)/follow-up duration] and entered in a voxelwise three-way analysis of covariance, with clinical status (healthy controls, mild cognitive impairment or Alzheimer's disease), disease progression (clinical conversion from healthy controls to mild cognitive impairment or Alzheimer's disease, or from mild cognitive impairment to Alzheimer's disease) and Pittsburgh compound B status (positive versus negative) as independent factors. Only a significant effect of the Pittsburgh compound B status was found: both Pittsburgh compound B-positive and -negative subjects showed a significant increase in amyloid-β deposition, with this increase being significantly higher in Pittsburgh compound B-positive individuals. This finding suggests either that Pittsburgh compound B-negative individuals have slower rates of amyloid-β accumulation than positive, or that the proportion of individuals showing significant increase in amyloid-β deposition, termed 'Pittsburgh compound B accumulators', is higher within the Pittsburgh compound B-positive group than within the Pittsburgh compound B-negative group. The bimodal distribution of the individual rates of neocortical amyloid-β accumulation observed support the existence of 'Pittsburgh compound B non-accumulators' and 'Pittsburgh compound B accumulators' and different clustering analyses led to a consistent threshold to separate these two subgroups (0.014-0.022 standardized uptake value ratio(pons)/year). The voxelwise three-way analysis of covariance was thus recomputed with the 'Pittsburgh compound B accumulators' only and the results were almost unchanged, with the Pittsburgh compound B-positive group showing higher accumulation than the Pittsburgh compound B-negative group. Finally, a significant negative correlation was found between Pittsburgh compound B rate of change and Pittsburgh compound B baseline burden, but only in the Pittsburgh compound B-positive group (r= -0.24; P=0.025). Higher rates of amyloid-β deposition are associated with higher amyloid-β burden suggesting that amyloid-β deposition does not reach a plateau when cognitive impairments manifest but is instead an ongoing process present even at the Alzheimer's disease stage. amyloid-β accumulation also seems to slow down at the latest stages of the process, i.e. in participants with the highest amyloid burden. Furthermore, this study identified the existence of Pittsburgh compound 'accumulators' and 'non-accumulators', notably within the Pittsburgh compound B-negative group, which may be a relevant concept for future studies.
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The widespread cerebral distribution of Aβ in later AD stages is well-established.
“The widespread cerebral distribution of Aβ in later AD stages is well-established3, 4”
From Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity (2017) · cites this paper as [4]
Previous longitudinal studies have either failed to detect an early increase in regional Aβ deposition or identified a rather large early stage Aβ region including the posterior temporal, inferior parietal, posterior cingulate, precuneus, and occipital areas.
“Previous longitudinal studies have either failed to detect an early increase in regional Aβ deposition16 or identified a rather large early stage Aβ region including the posterior temporal, inferior parietal, posterior cingulate, precuneus, and occipital areas4.”
From Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity (2017) · cites this paper as [4]
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Self-citationA European multicentre PET study of fibrillar amyloid in Alzheimer’s disease
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Alzheimer’s disease, cerebrovascular disease, and the β-amyloid cascade
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BDNF Val66Met, Aβ amyloid, and cognitive decline in preclinical Alzheimer's disease
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Aβ-amyloid and Tau Imaging in Dementia
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- Authors
- Villain, N., Chételat, G., Grassiot, B., Bourgeat, P., Jones, G., Ellis, K. A., Ames, D., Martins, R. N., Eustache, F., Salvado, O., Masters, C. L., Rowe, C. C., & Villemagne, V. L.
- Affiliations
- Inserm (FR)
- Commonwealth Scientific and Industrial Research Organisation (AU)
- Austin Hospital (AU)
- Mental Health Research Institute (AU)
- The University of Melbourne (AU)
- Edith Cowan University (AU)
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-05-23
- Volume
- 135
- Issue
- 7
- Pages
- 2126-2139
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W2116886795
- Cited by
- 255
- References
- 60
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 9 · 2023: 15 · 2022: 19 · 2021: 21 · 2020: 11 · 2019: 18 · 2018: 23 · 2017: 22 · 2016: 16 · 2015: 17 · 2014: 28 · 2013: 26 · 2012: 5
- FWCI
- 17.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Brain (publishedVersion)
- PubMed (publishedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Australasian Journal of Paramedicine (submittedVersion)
- HAL (submittedVersion, other-oa)
- Minerva Access (University of Melbourne) (submittedVersion)
- Funders
- Institut National de la Santé et de la Recherche Médicale
- Servier
- Institut Servier
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Medical Imaging Techniques and Applications
- Keywords
- amyloid-beta deposition, Alzheimer's disease, mild cognitive impairment, Pittsburgh compound B, amyloid PET, amyloid burden, healthy older adults, disease progression, neocortex, voxelwise analysis, standardized uptake value ratio, clustering, biomarkers
- MeSH terms
- Aged, Alzheimer Disease, Aniline Compounds, Brain Mapping, Carbon Radioisotopes, Female, Humans, Longitudinal Studies, Male, Neuropsychological Tests, Thiazoles, Case-Control Studies, Amyloid beta-Peptides, Disease Progression, Radiopharmaceuticals, Neocortex, Positron-Emission Tomography, Cognitive Dysfunction
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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