TY - JOUR T1 - Synaptic Vesicle Glycoprotein 2A Is Affected in the Central Nervous System of Mice with Huntington Disease and in the Brain of a Human with Huntington Disease Postmortem JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 942 LP - 947 DO - 10.2967/jnumed.121.262709 VL - 63 IS - 6 AU - Daniele Bertoglio AU - Jeroen Verhaeghe AU - Leonie Wyffels AU - Alan Miranda AU - Sigrid Stroobants AU - Ladislav Mrzljak AU - Celia Dominguez AU - Mette Skinbjerg AU - Jonathan Bard AU - Longbin Liu AU - Ignacio Munoz-Sanjuan AU - Steven Staelens Y1 - 2022/06/01 UR - http://jnm.snmjournals.org/content/63/6/942.abstract N2 - Synaptic dysfunction is a primary mechanism underlying Huntington disease (HD) progression. This study investigated changes in synaptic vesicle glycoprotein 2A (SV2A) density by means of 11C-UCB-J small-animal PET imaging in the central nervous system of mice with HD. Methods: Dynamic 11C-UCB-J small-animal PET imaging was performed at clinically relevant disease stages (at 3, 7, 10, and 16 mo) in the heterozygous knock-in Q175DN mouse model of HD and wild-type littermates (16–18 mice per genotype and time point). Cerebral 11C-UCB-J analyses were performed to assess genotypic differences during presymptomatic (3 mo) and symptomatic (7–16 mo) disease stages. 11C-UCB-J binding in the spinal cord was quantified at 16 mo. 3H-UCB-J autoradiography and SV2A immunofluorescence were performed postmortem in mouse and human brain tissues. Results: 11C-UCB-J binding was lower in symptomatic heterozygous mice than in wild-type littermates in parallel with disease progression (7 and 10 mo: P < 0.01; 16 mo: P < 0.0001). Specific 11C-UCB-J binding was detectable in the spinal cord, with symptomatic heterozygous mice displaying a significant reduction (P < 0.0001). 3H-UCB-J autoradiography and SV2A immunofluorescence corroborated the in vivo measurements demonstrating lower SV2A in heterozygous mice (P < 0.05). Finally, preliminary analysis of SV2A in the human brain postmortem suggested lower SV2A in HD gene carriers than in controls without dementia. Conclusion: 11C-UCB-J PET detected SV2A deficits during symptomatic disease in heterozygous mice in both the brain and the spinal cord and therefore may be suitable as a novel marker of synaptic integrity widely distributed in the central nervous system. On clinical application, 11C-UCB-J PET imaging may have promise for SV2A measurement in patients with HD during disease progression and after disease-modifying therapeutic strategies. ER -