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Cited by 117Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsCancer-related cognitive impairment studies

The DOI matches its Crossref record; 48 of the 48 references it cites were found in a registry or an index.

Hippocampal activation is associated with longitudinal amyloid accumulation and cognitive decline

Open access
Leal, Stephanie L, Landau, Susan M, Bell, Rachel K, Jagust, William J·2017·eLife
DOI 10.7554/elife.22978PMC PMC5325620
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Abstract

The amyloid hypothesis suggests that beta-amyloid (Aβ) deposition leads to alterations in neural function and ultimately to cognitive decline in Alzheimer’s disease. However, factors that underlie Aβ deposition are incompletely understood. One proposed model suggests that synaptic activity leads to increased Aβ deposition. More specifically, hyperactivity in the hippocampus may be detrimental and could be one factor that drives Aβ deposition. To test this model, we examined the relationship between hippocampal activity during a memory task using fMRI and subsequent longitudinal change in Aβ using PIB-PET imaging in cognitively normal older adults. We found that greater hippocampal activation at baseline was associated with increased Aβ accumulation. Furthermore, increasing Aβ accumulation mediated the influence of hippocampal activation on declining memory performance, demonstrating a crucial role of Aβ in linking hippocampal activation and memory. These findings support a model linking increased hippocampal activation to subsequent Aβ deposition and cognitive decline.

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Figure 1. Model-derived individual slopes for amyloid and memory change over time. (A) [11C] Pittsburgh Compound-B distribution volume ratio slope (PIB slope) for each participant over time, relative to baseline MRI (x = 0), where black line indicates average PIB slope, blue lines indicate little/no change in PIB, and red lines indicate positive PIB slope. The horizontal dotted line indicates the criterion for a positive PIB scan (1.06), (B) California Verbal Learning Test Long-Delay Free Recall slope (CVLT slope) for each participant over time, relative to baseline MRI (x = 0), where black line indicates average CVLT slope, red lines indicate negative CVLT slope, and blue lines indicate positive CVLT slope. All slopes were obtained from the linear mixed model. The following source data (Figure 1—source data 1) is relevant for Figures 1–4. DOI: http://dx.doi.org/10.7554/eLife.22978.004
Figure 1. Model-derived individual slopes for amyloid and memory change over time. (A) [11C] Pittsburgh Compound-B distribution volume ratio slope (PIB slope) for each participant over time, relative to baseline MRI (x = 0), where black line indicates average PIB slope, blue lines indicate little/no change in PIB, and red lines indicate positive PIB slope. The horizontal dotted line indicates the criterion for a positive PIB scan (1.06), (B) California Verbal Learning Test Long-Delay Free Recall slope (CVLT slope) for each participant over time, relative to baseline MRI (x = 0), where black line indicates average CVLT slope, red lines indicate negative CVLT slope, and blue lines indicate positive CVLT slope. All slopes were obtained from the linear mixed model. The following source data (Figure 1—source data 1) is relevant for Figures 1–4. DOI: http://dx.doi.org/10.7554/eLife.22978.004CC BY · PubMed Central
Figure 2. Relationship between brain activation at baseline and longitudinal amyloid accumulation. (a) Positive relationship between hippocampal activation (contrast values for subsequent hits versus misses) at baseline and [11C] Pittsburgh Compound-B distribution volume ratio (DVR) slopes (PIB slope measured as PIB DVR values over time) obtained from the linear mixed model, (b) No relationship between non-hippocampal activation (contrast values for subsequent hits versus misses in inferior frontal cortex and occipital cortex) at baseline and [11C] Pittsburgh Compound-B distribution volume ratio (DVR) slopes (PIB slope measured as PIB DVR values over time) obtained from the linear mixed model. DOI: http://dx.doi.org/10.7554/eLife.22978.006
Figure 2. Relationship between brain activation at baseline and longitudinal amyloid accumulation. (a) Positive relationship between hippocampal activation (contrast values for subsequent hits versus misses) at baseline and [11C] Pittsburgh Compound-B distribution volume ratio (DVR) slopes (PIB slope measured as PIB DVR values over time) obtained from the linear mixed model, (b) No relationship between non-hippocampal activation (contrast values for subsequent hits versus misses in inferior frontal cortex and occipital cortex) at baseline and [11C] Pittsburgh Compound-B distribution volume ratio (DVR) slopes (PIB slope measured as PIB DVR values over time) obtained from the linear mixed model. DOI: http://dx.doi.org/10.7554/eLife.22978.006CC BY · PubMed Central
Figure 3. Relationship between longitudinal amyloid accumulation and memory decline. Negative relationship between [11C] Pittsburgh Compound-B distribution volume ratio slopes (PIB slope) and California Verbal Learning Test Long-Delay Free Recall slope (CVLT slope measured as CVLT scores over time) obtained from the linear mixed model. DOI: http://dx.doi.org/10.7554/eLife.22978.008
Figure 3. Relationship between longitudinal amyloid accumulation and memory decline. Negative relationship between [11C] Pittsburgh Compound-B distribution volume ratio slopes (PIB slope) and California Verbal Learning Test Long-Delay Free Recall slope (CVLT slope measured as CVLT scores over time) obtained from the linear mixed model. DOI: http://dx.doi.org/10.7554/eLife.22978.008CC BY · PubMed Central
Figure 4. Mediation analysis between hippocampal activation, longitudinal amyloid accumulation, and memory decline. Mediation analysis with hippocampal activation at baseline (predictor, X), mediated by [11C] Pittsburgh Compound-B distribution volume ratio slopes (PIB Slope) (mediator, M), predicting California Verbal Learning Test Long-Delay Free Recall slope (CVLT Slope). Hippocampal activation positively predicted PIB Slope, PIB Slope negatively predicted CVLT Slope, which resulted in a significant mediation (see text for more details). DOI: http://dx.doi.org/10.7554/eLife.22978.010
Figure 4. Mediation analysis between hippocampal activation, longitudinal amyloid accumulation, and memory decline. Mediation analysis with hippocampal activation at baseline (predictor, X), mediated by [11C] Pittsburgh Compound-B distribution volume ratio slopes (PIB Slope) (mediator, M), predicting California Verbal Learning Test Long-Delay Free Recall slope (CVLT Slope). Hippocampal activation positively predicted PIB Slope, PIB Slope negatively predicted CVLT Slope, which resulted in a significant mediation (see text for more details). DOI: http://dx.doi.org/10.7554/eLife.22978.010CC BY · PubMed Central

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Metadata

Authors
Leal, S. L., Landau, S. M., Bell, R. K., & Jagust, W. J.
Affiliations
  • University of California, Berkeley (US)
  • Lawrence Berkeley National Laboratory (US)
Corresponding author
  • Leal, Stephanie L
  • Jagust, William J
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2017-02-08
Volume
6
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.22978
PMC
PMC5325620
OpenAlex
W2586682108
Cited by
117
References
48
Citations by year
2026: 5 · 2025: 10 · 2024: 11 · 2023: 16 · 2022: 11 · 2021: 16 · 2020: 14 · 2019: 20 · 2018: 10 · 2017: 4
FWCI
10.79
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institute on Aging (AG054116, AG034570)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Oncology › Cancer-related cognitive impairment studies
Keywords
hippocampal activation, amyloid-beta deposition, cognitive decline, Alzheimer's disease, amyloid hypothesis, memory performance, PiB PET, functional MRI, older adults, synaptic activity, longitudinal change
MeSH terms
Aged, Aged, 80 and over, Female, Hippocampus, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Amyloid beta-Peptides, Positron-Emission Tomography, Cognitive Dysfunction

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