Ryan S O'Dell1,2, Adam P Mecca1,2, Ming-Kai Chen3, Mika Naganawa3, Takuya Toyonaga3, Yihuan Lu3, Tyler A Godek1,2, Joanna E Harris1,2, Hugh H Bartlett1,2, Emmie R Banks1,2, Victoria L Kominek1,2, Wenzhen Zhao1,2, Nabeel B Nabulsi3, Jim Ropchan3, Yunpeng Ye3, Brent C Vander Wyk4, Yiyun Huang3, Amy F T Arnsten5, Richard E Carson3, Christopher H van Dyck6,7,8,9. 1. Alzheimer's Disease Research Unit, Yale University School of Medicine, One Church Street, 8th Floor, New Haven, CT, 06510, USA. 2. Department of Psychiatry, Yale University School of Medicine, 300 George Street, New Haven, CT, 06510, USA. 3. Department of Radiology and Biomedical Imaging, Yale University School of Medicine, P.O. Box 208048, New Haven, CT, 06520, USA. 4. Program on Aging, Yale University School of Medicine, P.O. Box 207900, New Haven, CT, 06520, USA. 5. Department of Neuroscience, Yale University School of Medicine, P.O. Box 208001, New Haven, CT, 06520, USA. 6. Alzheimer's Disease Research Unit, Yale University School of Medicine, One Church Street, 8th Floor, New Haven, CT, 06510, USA. christopher.vandyck@yale.edu. 7. Department of Psychiatry, Yale University School of Medicine, 300 George Street, New Haven, CT, 06510, USA. christopher.vandyck@yale.edu. 8. Department of Neuroscience, Yale University School of Medicine, P.O. Box 208001, New Haven, CT, 06520, USA. christopher.vandyck@yale.edu. 9. Department of Neurology, Yale University School of Medicine, P.O. Box 208018, New Haven, CT, 06520, USA. christopher.vandyck@yale.edu.
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.
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.
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