[C-11]UCB-J uptake and Ab accumulation across the cognitive spectrum

Objectives: [¹¹C]UCB-J is a PET radioligand which specifically binds to synaptic vesicle protein SV2A and is designed to reflect synaptic density. Synaptic loss along with beta-amyloid accumulation is a hallmark of Alzheimer’s disease. One of the aims of this ongoing study is to determine the relationship over time between synaptic density degradation as determined by lower [¹¹C]UCB-J binding and higher beta-amyloid burden as determined by [¹¹C]PiB binding.

Methods: Eighteen participants (69 ± 6 years old, 11 female/7 male) were recruited from the Wisconsin Alzheimer’s Disease Research Center and the Wisconsin Registry for Alzheimer’s Prevention study. Participants underwent comprehensive clinical and cognitive evaluation to determine the presence or absence of cognitive impairment according to NINDS/ADRDA criteria (McKahnn et al, 2011), and confirmed by a multidisciplinary consensus diagnostic panel. Each participant underwent [¹¹C]UCB-J dynamic imaging to assess synaptic density, [¹¹C]PiB dynamic imaging to assess beta-amyloid plaque accumulation. Volumetric MR imaging was performed to derive subject-specific regions of interest (ROIs) as well as to calculate the matrices required to transform the subject T1-w MR into MNI152 space. The PET images were smoothed, dynamically denoised, and registered to the T1-w MRI. Both scans were conducted over 70 minutes and binned into 5x2min and 12x5min frames. [¹¹C]PiB DVR images were created using Logan graphical analysis (t* = 30min, k2’ = 0.15min^-1, cerebellum grey matter reference region). Global amyloid burden was ascertained by taking the mean PiB DVR across eight bilateral regions of interest from the AAL atlas. Parametric [¹¹C]UCB-J DVR images were created using SRTM2 (cerebellum reference region, k2’ between 0.01 and 1.0 min-1 with an increment of 0.01). Subject-specific hippocampus ROIs were defined using FreeSurfer (v7) segmentation of the participant’s MR image.

Results: Among participants with cognitive impairment, [¹¹C]UCB-J DVR was lower in the hippocampus (0.54 ± 0.07) relative to the cognitively unimpaired group (0.85 ± 0.17) (P = 0.04). When[c1] the global [¹¹C]PiB DVR for all participants was compared to the [¹¹C]UCB-J DVR in the hippocampus, an overall inverse relationship was exhibited irrespective of cognitive status (R² = 0.10, P = 0.003) (Figure 1).

Conclusions: These preliminary data suggest a relationship between synaptic density and beta-amyloid accumulation as defined using [¹¹C]UCB-J and [¹¹C]PiB DVR measures, respectively. Future work will further elucidate this relationship in the context of Alzheimer’s disease progression. Figure 1: Cognitively impaired participants showed decreased [¹¹C]UCB-J uptake with variable [¹¹C]PiB binding while the overall group showed a relationship that suggests increased [¹¹C]PiB binding relates to decreased [¹¹C]UCB-J uptake, even among participants who were cognitively unimpaired.

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