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.
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.
Authors: José L Rozas; Leonardo Gómez-Sánchez; Cristina Tomás-Zapico; José J Lucas; Rafael Fernández-Chacón Journal: Biochem Soc Trans Date: 2010-04 Impact factor: 5.407
Authors: Austen J Milnerwood; Clare M Gladding; Mahmoud A Pouladi; Alexandra M Kaufman; Rochelle M Hines; Jamie D Boyd; Rebecca W Y Ko; Oana C Vasuta; Rona K Graham; Michael R Hayden; Timothy H Murphy; Lynn A Raymond Journal: Neuron Date: 2010-01-28 Impact factor: 17.173
Authors: Rui Lima; Eduardo D Gomes; Jorge R Cibrão; Luís A Rocha; Rita C Assunção-Silva; Cláudia S Rodrigues; Andreia Neves-Carvalho; Susana Monteiro; António J Salgado; Nuno A Silva Journal: NPJ Regen Med Date: 2021-03-02
Authors: Liliana B Menalled; Andrea E Kudwa; Sam Miller; Jon Fitzpatrick; Judy Watson-Johnson; Nicole Keating; Melinda Ruiz; Richard Mushlin; William Alosio; Kristi McConnell; David Connor; Carol Murphy; Steve Oakeshott; Mei Kwan; Jose Beltran; Afshin Ghavami; Dani Brunner; Larry C Park; Sylvie Ramboz; David Howland Journal: PLoS One Date: 2012-12-20 Impact factor: 3.240
Authors: Taneli Heikkinen; Kimmo Lehtimäki; Nina Vartiainen; Jukka Puoliväli; Susan J Hendricks; Jack R Glaser; Amyaouch Bradaia; Kristian Wadel; Chrystelle Touller; Outi Kontkanen; Juha M Yrjänheikki; Bruno Buisson; David Howland; Vahri Beaumont; Ignacio Munoz-Sanjuan; Larry C Park Journal: PLoS One Date: 2012-12-20 Impact factor: 3.240
Authors: Daniele Bertoglio; Nicolas Halloin; Stef De Lombaerde; Aleksandar Jankovski; Jeroen Verhaeghe; Charles Nicaise; Steven Staelens Journal: J Nucl Med Date: 2022-01-13 Impact factor: 11.082
Authors: Takuya Toyonaga; Arman Fesharaki-Zadeh; Stephen M Strittmatter; Richard E Carson; Zhengxin Cai Journal: Front Neurosci Date: 2022-03-08 Impact factor: 4.677