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

ABSTRACT:

Background

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

Methods

We measured SV2A binding ([¹¹C]UCB-J) and A? 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 A? deposition and SV2A binding in hippocampus. Exploratory analyses examined correlations between both global and regional A? 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 A? 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 A? deposition and regional SV2A binding in either diagnostic group. ROI-based analyses of the association between regional A? deposition and SV2A binding also revealed no consistent pattern but suggested a "paradoxical" positive association between local A? deposition and SV2A binding in the hippocampus.

Conclusions

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

SUBMITTER: O'Dell RS 

PROVIDER: S-EPMC7786921 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature