In vivo measurement of widespread synaptic loss in Alzheimer's disease with SV2A PET

Abstract

Introduction: Synaptic loss is a robust and consistent pathology in Alzheimer's disease (AD) and the major structural correlate of cognitive impairment. Positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) has emerged as a promising biomarker of synaptic density.

Methods: We measured SV2A binding in 34 participants with early AD and 19 cognitively normal (CN) participants using [¹¹ C]UCB-J PET and a cerebellar reference region for calculation of the distribution volume ratio.

Results: We observed widespread reductions of SV2A binding in medial temporal and neocortical brain regions in early AD compared to CN participants. These reductions were largely maintained after correction for volume loss and were more extensive than decreases in gray matter volume.

Conclusion: We were able to measure widespread synaptic loss due to AD using [¹¹ C]UCB-J PET. Future studies will continue to evaluate the utility of SV2A PET for tracking AD progression and for monitoring potential therapies.

Keywords: Alzheimer's disease; SV2A; [11C]UCB-J | PET; synaptic density.

FIGURE 1

Comparison of synaptic density in AD and CN groups using DVR _Cb (A) before and (B) after partial volume correction (PVC). ^* P < 0.05, ^† P < 0.001, ^‡ P < 0.0001 for post hoc t tests comparing AD (n = 19) and CN (n = 34) groups. False discovery rate correction for multiple comparisons is shown in Table 2. Dots represent the DVR _Cb for each participant. Error bars represent standard deviations. Abbreviations: DVR _Cb, distribution volume ratio using a cerebellum reference region; CN, cognitively normal, AD, Alzheimer's disease.

FIGURE 2

Synaptic density (DVR _Cb) in AD and CN groups determined by [¹¹C]UCB‐J PET. Coronal sections of average parametric images of DVR _Cb for (A) 19 CN participants and (B) 34 AD participants. Average images are created after co‐registration to a common MNI template. The average parametric PET scans are displayed in pseudo‐color representing [¹¹C]UCB‐J binding to SV2A (DVR _Cb) and overlaid on the MNI template T1 MRI. Lower DVR _Cb in AD compared to CN participants was apparent in the medial temporal lobe and throughout the cortex and subcortex.

FIGURE 3

Effect‐size maps of synaptic density (DVR _Cb) and brain volume between AD and CN groups. Effect sizes for differences in AD compared to CN groups were calculated for (A) uncorrected [¹¹C]UCB‐J PET, (B) PVC [¹¹C]UCB‐J PET, and brain volume (C) in all FreeSurfer regions. The color scale represents Cohen's d for the comparison between CN and AD group. Effect size statistics are displayed only for regions that had an uncorrected P < 0.05. Contrast is for CN>AD. Abbreviations: CN, cognitively normal; AD, Alzheimer's disease; PET, positron emission tomography; DVR _Cb, distribution volume ratio using a cerebellum reference region.