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. 2021 Jan 5;13(1):11.
doi: 10.1186/s13195-020-00742-y.

Association of Aβ deposition and regional synaptic density in early Alzheimer's disease: a PET imaging study with [11C]UCB-J

Ryan S O'Dell  1   2 , Adam P Mecca  1   2 , Ming-Kai Chen  3 , Mika Naganawa  3 , Takuya Toyonaga  3 , Yihuan Lu  3 , Tyler A Godek  1   2 , Joanna E Harris  1   2 , Hugh H Bartlett  1   2 , Emmie R Banks  1   2 , Victoria L Kominek  1   2 , Wenzhen Zhao  1   2 , Nabeel B Nabulsi  3 , Jim Ropchan  3 , Yunpeng Ye  3 , Brent C Vander Wyk  4 , Yiyun Huang  3 , Amy F T Arnsten  5 , Richard E Carson  3 , Christopher H van Dyck  6   7   8   9
Affiliations

Association of Aβ deposition and regional synaptic density in early Alzheimer's disease: a PET imaging study with [11C]UCB-J

Ryan S O'Dell et al. Alzheimers Res Ther. .

Abstract

Background: Attempts to associate amyloid-β (Aβ) pathogenesis with synaptic loss in Alzheimer's disease (AD) have thus far been limited to small numbers of postmortem studies. Aβ plaque burden is not well-correlated with indices of clinical severity or neurodegeneration-at least in the dementia stage-as deposition of Aβ reaches a ceiling. In this study, we examined in vivo the association between fibrillar Aβ deposition and synaptic density in early AD using positron emission tomography (PET). We hypothesized that global Aβ deposition would be more strongly inversely associated with hippocampal synaptic density in participants with amnestic mild cognitive impairment (aMCI; a stage of continued Aβ accumulation) compared to those with dementia (a stage of relative Aβ plateau).

Methods: We measured SV2A binding ([11C]UCB-J) and Aβ deposition ([11C]PiB) in 14 participants with aMCI due to AD and 24 participants with mild AD dementia. Distribution volume ratios (DVR) with a cerebellar reference region were calculated for both tracers to investigate the association between global Aβ deposition and SV2A binding in hippocampus. Exploratory analyses examined correlations between both global and regional Aβ deposition and SV2A binding across a broad range of brain regions using both ROI- and surface-based approaches.

Results: We observed a significant inverse association between global Aβ deposition and hippocampal SV2A binding in participants with aMCI (r = - 0.55, P = 0.04), but not mild dementia (r = 0.05, P = 0.82; difference statistically significant by Fisher z = - 1.80, P = 0.04). Exploratory analyses across other ROIs and whole brain analyses demonstrated no broad or consistent associations between global Aβ deposition and regional SV2A binding in either diagnostic group. ROI-based analyses of the association between regional Aβ deposition and SV2A binding also revealed no consistent pattern but suggested a "paradoxical" positive association between local Aβ deposition and SV2A binding in the hippocampus.

Conclusions: Our findings lend support to a model in which fibrillar Aβ is still accumulating in the early stages of clinical disease but approaching a relative plateau, a point at which Aβ may uncouple from neurodegenerative processes including synaptic loss. Future research should investigate the relationship between Aβ deposition and synaptic loss in larger cohorts beginning preclinically and followed longitudinally in conjunction with other biomarkers.

Keywords: Alzheimer’s disease; Aβ; SV2A; Synaptic density; [11C] PiB PET; [11C]UCB-J PET.

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Conflict of interest statement

APM, REC, and CHvD report grants from National Institutes of Health for the conduct of the study. APM reports grants for clinical trials from Genentech and Eisai outside the submitted work. MKC reports research support from the Dana Foundation and research support from Eli Lilly and clinical trials from Merck outside the submitted work. YH reports research grants from the UCB and Eli Lilly outside the submitted work. YH, NBN, and REC have a patent for a newer version of the tracer. REC is a consultant for Rodin Therapeutics and has received research funding from UCB. REC reports having received grants from AstraZeneca, Astellas, Eli Lilly, Pfizer, Taisho, and UCB, outside the submitted work. CHvD reports consulting fees from Kyowa Kirin, Roche, Merck, Eli Lilly, and Janssen and grants for clinical trials from Biogen, Novartis, Eli Lilly, Merck, Eisai, Janssen, Roche, Genentech, Toyama, and Biohaven, outside the submitted work. No other disclosures are reported.

Figures

Fig. 1
Fig. 1
Comparison of SV2A and Aβ deposition in CN, aMCI, and dementia groups. Coronal sections of average parametric images of DVR for a [11C]UCB-J and b [11C] PiB in CN, aMCI, and dementia groups. Averaged images were created after co-registration to a common MNI template and overlaid on an MNI template T1 MRI. Parametric images adhere to radiological convention, with orientation denoted in the first coronal section of each image series. Quantification of between-group differences in c [11C]UCB-J DVR and d [11C] PiB DVR across all ROIs. One-way ANOVAs within each ROI with post hoc unpaired t-tests, FDR-corrected for multiple comparisons (3 comparisons for diagnostic groups), demonstrated significantly lower [11C]UCB-J DVR and significantly higher [11C] PiB DVR in both the aMCI and dementia participants (as compared to CN) across most analyzed regions. No group differences were observed in either SV2A or Aβ binding between aMCI and dementia participants across all analyzed ROIs. # denotes significant post hoc group differences between aMCI and CN. # P < 0.05, ## P < 0.001, ### P < 0.0001. * denotes significant group post hoc differences between dementia and CN. * P < 0.05, ** P < 0.001, *** P < 0.0001. Abbreviations: DVR, distribution volume ratio using a whole cerebellum reference region; PCC, posterior cingulate cortex, aMCI: amnestic mild cognitive impairment; CN: cognitively normal; MNI, Montreal Neurological Institute; MRI, magnetic resonance image; PET, positron emission tomography; ROI, region of interest; SV2A, synaptic vesicle glycoprotein 2A; PiB, Pittsburgh Compound B; FDR, false discovery rate
Fig. 2
Fig. 2
Correlation of global Aβ deposition and hippocampal SV2A in aMCI and dementia due to AD. Scatter plot with best-fit lines depicts a significant inverse association between global Aβ deposition and hippocampal SV2A in participants with aMCI (green) but not with dementia (red). Correlation coefficients were calculated from separate univariate linear regression analyses in each group with associated two-tailed P values, without correction for multiple comparisons. Global Aβ deposition was calculated by averaging values of [11C] PiB DVR from the bilateral prefrontal, lateral temporal, posterior cingulate/precuneus, and lateral parietal ROIs, weighted by volume. Green circles denote DVR values for aMCI participants, while red circles denote DVR values for participants with dementia. Abbreviations: DVR, distribution volume ratio using a whole cerebellum reference region; aMCI: amnestic mild cognitive impairment; SV2A, synaptic vesicle glycoprotein 2A; PiB, Pittsburgh Compound B
Fig. 3
Fig. 3
Brain maps of correlations between global Aβ deposition and SV2A in aMCI and dementia. Brain maps were created by producing images with the voxels in each FreeSurfer region set uniformly to the calculated Pearson r for that region and overlaid on an MNI template T1 MRI. Correlations were across all 84 lateralized FreeSurfer brain regions and displayed only for regions with uncorrected P < 0.05 in both the a aMCI and b dementia diagnostic groups. MR image slices adhere to radiological convention, with orientation denoted in the first coronal section of each image series. Abbreviations: DVR, distribution volume ratio using a whole cerebellum reference region; aMCI, amnestic mild cognitive impairment
Fig. 4
Fig. 4
Brain maps of correlations between regional Aβ deposition and SV2A in aMCI and dementia. Brain maps were created by producing images with the voxels in each FreeSurfer region set uniformly to the calculated Pearson r for that region and overlaid on an MNI template T1 MRI. Correlations were across all 84 lateralized FreeSurfer brain regions and displayed only for regions with uncorrected P < 0.05 in both the a aMCI and b dementia diagnostic groups. MR image slices adhere to radiological convention, with orientation denoted in the first coronal section of each image series. Abbreviations: DVR, distribution volume ratio using a whole cerebellum reference region; aMCI, amnestic mild cognitive impairment
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