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Cited by 165Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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Local and distant relationships between amyloid, tau and neurodegeneration in Alzheimer's Disease

Open access
Iaccarino, Leonardo, Tammewar, Gautam, Ayakta, Nagehan, Baker, Suzanne L., Bejanin, Alexandre, Boxer, Adam L., Gorno-Tempini, Maria Luisa, Janabi, Mustafa, Kramer, Joel H., Lazaris, Andreas, Lockhart, Samuel N., Miller, Bruce L., Miller, Zachary A., O'Neil, James P., Ossenkoppele, Rik, Rosen, Howard J., Schonhaut, Daniel R., Jagust, William J., Rabinovici, Gil D.·2018·NeuroImage: Clinical
DOI 10.1016/j.nicl.2017.09.016PMC PMC5684433
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Abstract

The relationships between β-amyloid (Aβ), tau and neurodegeneration within Alzheimer's Disease pathogenesis are not fully understood. To explore these associations in vivo, we evaluated 30 Aβ PET-positive patients (mean ± sd age 62.4 ± 8.3) with mild probable AD and 12 Aβ PET-negative healthy controls (HC) (mean ± sd age 77.3 ± 6.9) as comparison. All participants underwent 3 T MRI, 11C-PiB (Aβ) PET and 18F-AV1451 (tau) PET. Multimodal correlation analyses were run at both voxel- and region-of-interest levels. 11C-PiB retention in AD showed the most diffuse uptake pattern throughout association neocortex, whereas 18F-AV1451 and gray matter volume reduction (GMR) showed a progressive predilection for posterior cortices (p<0.05 Family-Wise Error-[FWE]-corrected). Voxel-level analysis identified negative correlations between 18F-AV1451 and gray matter peaking in medial and infero-occipital regions (p<0.01 False Discovery Rate-[FDR]-corrected). 18F-AV1451 and 11C-PiB were positively correlated in right parietal and medial/inferior occipital regions (p<0.001 uncorrected). 11C-PiB did not correlate with GMR at the voxel-level. Regionally, 18F-AV1451 was largely associated with local/adjacent GMR whereas frontal 11C-PiB correlated with GMR in posterior regions. These findings suggest that, in mild AD, tau aggregation drives local neurodegeneration, whereas the relationships between Aβ and neurodegeneration are not region specific and may be mediated by the interaction between Aβ and tau.

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Figures

Fig. 1 Group-level pathology accumulation and neurodegeneration. Figure showing significant amyloid accumulation (panel A, p<0.05 FWE-corrected), tau accumulation (panel B, p<0.05 FWE-corrected) and Gray matter volume reduction (panel C, p<0.0001 uncorrected). Thresholded SPM-t maps are surface rendered on an ICBM152 template with BrainNet Viewer (see Visualization section).
Fig. 1 Group-level pathology accumulation and neurodegeneration. Figure showing significant amyloid accumulation (panel A, p<0.05 FWE-corrected), tau accumulation (panel B, p<0.05 FWE-corrected) and Gray matter volume reduction (panel C, p<0.0001 uncorrected). Thresholded SPM-t maps are surface rendered on an ICBM152 template with BrainNet Viewer (see Visualization section).CC BY-NC-ND · PubMed Central
Fig. 2 BPM analysis of protein-neurodegeneration relationships. Figure showing the results of the local multimodal Protein-Neurodegeneration BPM analysis at the voxel-level. Colors index three different statistical thresholds ranging from more liberal (p<0.01 and p<0.001 uncorrected for multiple comparisons) to a more conservative threshold (p<0.01 FDR corrected for multiple comparisons). Thresholded SPM-t maps were binarized and summed, then surface rendered on an ICBM152 template with BrainNet Viewer (see Visualization section). Panel A: 18F-AV1451 SUVR z-maps explaining GMV z-maps, controlling for age, sex and 11C-PiB DVR z-maps as imaging covariate. Panel B: 11C-PiB DVR z-maps explaining GMV z-maps, controlling for age, sex and 18F-AV1451 SUVR z-maps as imaging covariate.
Fig. 2 BPM analysis of protein-neurodegeneration relationships. Figure showing the results of the local multimodal Protein-Neurodegeneration BPM analysis at the voxel-level. Colors index three different statistical thresholds ranging from more liberal (p<0.01 and p<0.001 uncorrected for multiple comparisons) to a more conservative threshold (p<0.01 FDR corrected for multiple comparisons). Thresholded SPM-t maps were binarized and summed, then surface rendered on an ICBM152 template with BrainNet Viewer (see Visualization section). Panel A: 18F-AV1451 SUVR z-maps explaining GMV z-maps, controlling for age, sex and 11C-PiB DVR z-maps as imaging covariate. Panel B: 11C-PiB DVR z-maps explaining GMV z-maps, controlling for age, sex and 18F-AV1451 SUVR z-maps as imaging covariate.CC BY-NC-ND · PubMed Central
Fig. 3 BPM analysis of amyloid-tau local relationships. Figure showing the results of the local amyloid-tau relationships BPM analysis. This model used the 11C-PiB DVR z-maps as explanatory variable and 18F-AV1451 SUVR z-maps as dependent variable, both PVC-corrected, controlling for age and sex. Colors index three different statistical thresholds ranging from more liberal (p<0.01 and p<0.001 uncorrected for multiple comparisons) to a more conservative threshold (p<0.01 FDR corrected for multiple comparisons). Thresholded SPM-t maps were binarized and summed, then surface rendered on a ICBM152 template with BrainNet Viewer (see Visualization section).
Fig. 3 BPM analysis of amyloid-tau local relationships. Figure showing the results of the local amyloid-tau relationships BPM analysis. This model used the 11C-PiB DVR z-maps as explanatory variable and 18F-AV1451 SUVR z-maps as dependent variable, both PVC-corrected, controlling for age and sex. Colors index three different statistical thresholds ranging from more liberal (p<0.01 and p<0.001 uncorrected for multiple comparisons) to a more conservative threshold (p<0.01 FDR corrected for multiple comparisons). Thresholded SPM-t maps were binarized and summed, then surface rendered on a ICBM152 template with BrainNet Viewer (see Visualization section).CC BY-NC-ND · PubMed Central
Fig. 4 Multimodal relationships between biomarkers at the ROI level. Figure showing multimodal inter-regional relationships between 11C-PiB DVR, 18F-AV1451 SUVR and GMV z-scores estimated in native space. Correlation matrices are rendered on a ICBM152 template and are shown in bilateral and top axial view with BrainNet Viewer (see Visualization section). Panels A–C: Each node represents a Freesurfer-derived brain region (Desikan Atlas, see Methods). Nodes color index Macroregions. Edges color index the sign of the correlation, where BLUE = negative and RED = positive. Each edge represents a significant (p<0.001 uncorrected for multiple comparisons) inter-regional correlation. (A) 11C-PiB DVR z-scores explaining GMV z-scores; (B) 18F-AV1451 SUVR z-scores explaining GMV z-scores; (C) 11C-PiB DVR z-scores explaining 18F-AV1451 SUVR z-scores (Both PVC-corrected). Panel D: Stacked barplots showing the frequency of “Within-Lobe” (black) and “Between-Lobes” (orange) associations of both 11C-PiB DVR z-scores and 18F-AV1451 SUVR z-scores with GMV z-scores. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Fig. 4 Multimodal relationships between biomarkers at the ROI level. Figure showing multimodal inter-regional relationships between 11C-PiB DVR, 18F-AV1451 SUVR and GMV z-scores estimated in native space. Correlation matrices are rendered on a ICBM152 template and are shown in bilateral and top axial view with BrainNet Viewer (see Visualization section). Panels A–C: Each node represents a Freesurfer-derived brain region (Desikan Atlas, see Methods). Nodes color index Macroregions. Edges color index the sign of the correlation, where BLUE = negative and RED = positive. Each edge represents a significant (p<0.001 uncorrected for multiple comparisons) inter-regional correlation. (A) 11C-PiB DVR z-scores explaining GMV z-scores; (B) 18F-AV1451 SUVR z-scores explaining GMV z-scores; (C) 11C-PiB DVR z-scores explaining 18F-AV1451 SUVR z-scores (Both PVC-corrected). Panel D: Stacked barplots showing the frequency of “Within-Lobe” (black) and “Between-Lobes” (orange) associations of both 11C-PiB DVR z-scores and 18F-AV1451 SUVR z-scores with GMV z-scores. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)CC BY-NC-ND · PubMed Central
Fig. 5 Intra-modality regional correlations. Figure showing results of intra-modal regional correlation analyses. TOP: Triangle matrices depict the intra-modal regional correlations for each biomarker studied. Color scale index partial correlation Spearman coefficient strength. Matrices are filtered to show only significant (p<0.001) associations. The diagonal visible in the right lower part of all the triangles represents associations between each region and the respective contra-lateral homologue. BOTTOM: Binarized thresholded matrices are respectively rendered on a 3D surface for visualization purposes with BrainNet Viewer (see Visualization section). Each edge represents a significant inter-regional correlation (i.e. a square in the respective matrix). Within the 18F-AV1451 SUVR z-scores matrix there was a single negative inter-hemispheric correlation, which was not color-coded for the purpose of visualization. Legend: LH = left hemisphere, RH = right hemisphere, L = limbic, I = insula, C = cingulate, F = frontal, T = temporal, P = parietal, O = occipital.
Fig. 5 Intra-modality regional correlations. Figure showing results of intra-modal regional correlation analyses. TOP: Triangle matrices depict the intra-modal regional correlations for each biomarker studied. Color scale index partial correlation Spearman coefficient strength. Matrices are filtered to show only significant (p<0.001) associations. The diagonal visible in the right lower part of all the triangles represents associations between each region and the respective contra-lateral homologue. BOTTOM: Binarized thresholded matrices are respectively rendered on a 3D surface for visualization purposes with BrainNet Viewer (see Visualization section). Each edge represents a significant inter-regional correlation (i.e. a square in the respective matrix). Within the 18F-AV1451 SUVR z-scores matrix there was a single negative inter-hemispheric correlation, which was not color-coded for the purpose of visualization. Legend: LH = left hemisphere, RH = right hemisphere, L = limbic, I = insula, C = cingulate, F = frontal, T = temporal, P = parietal, O = occipital.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Iaccarino, L., Tammewar, G., Ayakta, N., Baker, S. L., Bejanin, A., Boxer, A. L., Gorno-Tempini, M. L., Janabi, M., Kramer, J. H., Lazaris, A., Lockhart, S. N., Miller, B. L., Miller, Z. A., O'Neil, J. P., Ossenkoppele, R., Rosen, H. J., Schonhaut, D. R., Jagust, W. J., & Rabinovici, G. D.
Affiliations
  • Vita-Salute San Raffaele University (IT)
  • University of California, San Francisco (US)
  • Lawrence Berkeley National Laboratory (US)
  • University of California, Berkeley (US)
Corresponding author
Iaccarino, Leonardo
ORCID
Venue
NeuroImage: Clinical
Publisher
Elsevier BV
Published
2018
Volume
17
Pages
452-464
ISSN
2213-1582 (ISSN-L)
DOI
10.1016/j.nicl.2017.09.016
PMC
PMC5684433
OpenAlex
W2756641284
Cited by
165
References
85
Citations by year
2026: 10 · 2025: 13 · 2024: 22 · 2023: 18 · 2022: 22 · 2021: 18 · 2020: 20 · 2019: 25 · 2018: 17
FWCI
12.55
Type
journal article
Language
en
Open access
Licence
Locations
  • NeuroImage Clinical (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • 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)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
  • University of California
  • FP7 People: Marie-Curie Actions (628812)
  • National Institutes of Health (K23-AG048291, R01-AG038791, U01-AG045390, U54-NS092089)
  • Tau Consortium
  • National Institute on Aging (F32-AG050389, P50-AG023501, R01-AG034570, R01-AG045611)
  • John Douglas French Alzheimer&apos;s Foundation
  • National Institute of Neurological Disorders and Stroke (R01-NS050915)
  • Ministero dell’Istruzione, dell’Università e della Ricerca
  • Alzheimer&apos;s Association
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, amyloid-beta, tau protein, neurodegeneration, 11C-PiB PET, gray matter volume reduction
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Brain, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Neural Pathways, Amyloid beta-Peptides, tau Proteins, Positron-Emission Tomography

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