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

Introduction Synaptic loss is an early pathology in Alzheimer's disease (AD) and the major structural correlate of cognitive impairment. We have recently demonstrated extensive synaptic loss in the medial temporal and neocortical regions of participants with AD, using in vivo positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A), a promising biomarker of synaptic density. Attempts to associate amyloid-β (Aβ) pathogenesis with synaptic loss in AD however, 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 vivothe association between fibrillar Aβ deposition and synaptic density in early AD using [11C]PiB and [11C]UCB-J 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 [11C]UCB-J (for SV2A) and [11C]PiB (Aβ deposition) binding were measured in 14 participants with aMCI due to AD, 24 participants with mild AD dementia, and 19 cognitively normal (CN) participants aged 55-85 years. For [11C]PiB data analysis, parametric images of binding potential (BPND) were generated using SRTM2 with cerebellum as a reference region and converted to distribution volume ratios (DVR). For [11C]UCB-J, BPNDwas computed using SRTM2 with a shrunken centrum semiovale reference region and converted to DVR with a cerebellum reference region. For the primary analysis of the association between global Aβ deposition and hippocampal SV2A binding in participants with aMCI and dementia, separate univariate regression analyses were performed for each diagnostic group with Pearson r and associated two-tailed P values reported for each model. Fisher z-transformation assessed significant differences in correlation coefficients between the aMCI and dementia groups, with one-tailed P values reported. 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. Global Aβ deposition was determined for a composite of regions commonly affected by Aβ deposition in AD which included: prefrontal, lateral temporal, posterior cingulate/precuneus, and lateral parietal ROIs. Results The AD group showed significant widespread reductions in cortical and subcortical synaptic density, most pronounced in the medial temporal lobe, and significantly elevated cortical amyloid in regions commonly affected by AD pathology (Figure 1). 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; Figure 2).This stronger association was observed to survive partial volume correction (aMCI r= -0.56, P= 0.04; dementia r= -0.01, P= 0.96; Fisher z= -1.67, P= 0.047). 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 nominal inverse association in the dementia group between local Aβ deposition and SV2A binding in medial occipital cortex and a more compelling, larger positive correlation between local Aβ accumulation and synaptic density in hippocampus (Table 1). Conclusions To our knowledge, we have conducted the first in vivo study investigating the relationship between Aβ deposition and synaptic alterations in participants with AD. We observed significant inverse associations between measures of global Aβ deposition and hippocampal synaptic density within participants with aMCI but not with dementia. Our findings lend support to a model in which fibrillar Aβ may 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 shouldinvestigate the relationship between Aβ deposition and synaptic loss in larger cohorts beginning preclinically and followed longitudinally in conjunction with other biomarkers. Funding P50-AG047270 (CHvD), P30-AG066508 [CHvD], K23-AG057794 (APM), R01-AG052560 (REC, CHV), R01-AG062276 (CHvD), Dana Foundation (MKC), T32-MH019961 (RSO), and Thomas P. Detre Fellowship (RSO).