Objective: To assess synapse loss in vivo in late premanifest Huntington’s disease (HD) subjects using [¹⁸F]SynVesT-1 positron emission tomography (PET).

Background: Synaptic damage is believed to play a major role in HD pathophysiology and may arise before medium spiny neuron degeneration. Synaptic vesicle protein 2A (SV2A), which is present in presynaptic terminals throughout the brain, can be visualized using SV2A-targeted PET radioligands. A previous [¹¹C]UCB-J PET study in a small number of premanifest HD mutation carriers found significant SV2A loss in caudate and putamen. Here, we assessed SV2A loss in a large cohort of premanifest HD subjects using [¹⁸F]SynVesT-1 PET.

Method: Late premanifest HD subjects (HD-Integrated Staging System [HD-ISS] stage < 2; CAP₁₀₀ score > 70) and age- and sex-matched healthy controls (HC) underwent clinical testing, 90-minute dynamic [¹⁸F]SynVesT-1 PET with arterial sampling and volumetric MRI. Distribution volumes (V_T) were calculated using a one-tissue compartment model, with and without region-based voxelwise partial volume correction (PVC).

Results: Twenty premanifest HD subjects (11 female; age 43.3 ± 10.2 years; 19 HD-ISS stage 1, 1 HD-ISS stage 0; CAP₁₀₀ score 86.4 ± 12.1) and 17 HC (10 female; 42.2 ± 10.5 years) were included. Compared to HC, premanifest HD subjects scored significantly worse on MoCA, verbal fluency, trail making test A, UHDRS total motor score and PBA-S. Volume of interest (VOI)-based volumetry showed volume loss in premanifest HD compared to HC in caudate (-19.8 ± 10.5%; p<0.001), putamen (-17.8 ± 9.9%; p<0.001) and pallidum (-11.2 ± 8.3%; p<0.001). Voxel-based morphometry confirmed decreased caudate and putamen volume in premanifest HD. VOI-based [¹⁸F]SynVesT-1 V_T was lower in premanifest HD subjects compared to HC in caudate (-17.0 ± 8.8%; p<0.001), putamen (-14.9 ± 7.9%; p<0.001) and pallidum (-11.6 ± 6.5%; p<0.001). After PVC [¹⁸F]SynVesT-1 V_T remained significantly lower in caudate (-13.1 ± 7.4%; p<0.001), putamen (-14.4 ± 7.4%; p<0.001) and pallidum (-11.5 ± 7.0%; p=0.001). Voxel-based analysis confirmed a decrease in [¹⁸F]SynVesT-1 V_T with clusters comprising caudate and putamen.

Conclusion: In this first [¹⁸F]SynVesT-1 PET study in HD, we find significant synaptic loss in caudate, putamen and pallidum in the late premanifest phase.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/pet-imaging-of-presynaptic-terminals-with-18fsynvest-1-in-premanifest-huntingtons-disease/