Multi-Modal PET Imaging to Characterize the Relationship between Alzheimer’s Disease Pathology and Synaptic Density
Abstract
Purpose
Alzheimer’s disease (AD) is the most common form of dementia, exhibiting two characteristic brain neuropathologies - amyloid plaques (A) and neurofibrillary tau tangles (T) - hypothesized to disrupt neuronal function. Positron emission tomography (PET) is the gold standard for in vivo pathology measurement, providing spatial visualization and quantitative outcomes. Synaptic density imaging with PET radiotracer [11C]UCB-J is a novel method of imaging structural neurodegeneration. This study evaluates the relationship between synaptic density and AD pathology using multi-modal PET neuroimaging as an in vivo biomarker.
Methods
72 participants (55.6% female; average age=72.0 (7.6) years) completed T1-weighted structural MRIs, [11C]PiB amyloid (A), [18F]MK-6240 tau (T), and [11C]UCB-J synaptic density PET. PET scans were coregistered to MRIs and intensity normalized using tracer-specific reference regions. MRIs were parcellated into brain regions using FreeSurfer. UCB-J distribution volume ratios (DVRs) were calculated as an index of synaptic density for 8 regions associated with AD neurodegeneration. Standard diagnostic measures were calculated for A (global PiB DVR) and T (MK-6240 standardized uptake value ratio (SUVR) in entorhinal cortex), and participants were grouped by A/T positivity status using published thresholds. Synaptic density was evaluated across A/T status using Wilcoxon rank sum tests (A-/T- = healthy control) and linear regression (UCB-J DVR ~ A DVR, UCB-J DVR ~ T SUVR).
Results
A/T pathology groups differed significantly in synaptic density; the largest effect sizes were observed for A+/T+ vs. A-/T- contrasts of the parahippocampal gyrus (Cohen's d = -1.24, p<0.001) and the hippocampus (Cohen's d = -1.10, p<0.001). Similarly, when modeling UCB-J DVR with A DVR or T SUVR, all regions demonstrated standardized beta coefficients < -0.3, except the amygdala (T SUVR beta = -0.27).
Conclusion
Synaptic density, measured with [11C]UCB-J PET, is lower in the presence of AD pathology. Multi-modal PET imaging can provide complementary information about disease progression.