Objective: To assess synaptic damage in early stages of Huntington’s disease (HD) in vivo.

Background: Synaptic damage has long been suspected to play a major role in the pathophysiology of HD, but in vivo evidence in humans is limited.

Method: Eighteen HD mutation carriers (51.4 ± 11.6 years; 6F/12M; 7 premanifest, 11 early manifest [7 Shoulson-Fahn stage 1, 4 stage 2]; CAG repeat 41.9 ± 1.7; disease burden 317 ± 50) and 15 age- and gender-matched healthy controls (52.3 ± 3.5 years; 4F/11M) participated in a PET/MR study with ¹¹C-UCB-J, a radioligand for the ubiquitous presynaptic terminal marker SV2A. We also performed ¹⁸F-FDG PET in all subjects, as regional cerebral glucose consumption is thought to largely reflect synaptic activity. All subjects were clinically assessed for motor and non-motor manifestations of HD. Volumes of interest were delineated based on individual 3D T1 MRI. SUVR-1 images were calculated for ¹¹C-UCB-J with the centrum semiovale as reference region. ¹⁸F-FDG PET images were normalized to the pons. PET images were corrected for partial volume effects.

Results: ¹¹C-UCB-J PET showed loss of SV2A binding in the HD group in putamen (-28%, p<0.001),  caudate (-25%, p<0.001), pallidum (-24%, p<0.001), frontal (-8%, p=0.004) and parietal cortex (-9%, p=0.002) and cerebellum (-11%,p=0.002). By contrast, ¹⁸F-FDG PET only showed significantly lower uptake in caudate and putamen (both -31%, p<0.001). In the premanifest subgroup, ¹¹C-UCB-J PET and ¹⁸F-FDG PET showed significant reductions in putamen and caudate only. In the HD group, ¹¹C-UCB-J binding in caudate correlated with UHDRS motor score (r_p= -0.70, p=0.001), SDMT (r_p=0.67, p=0.002) and AVLT sum (r_p=0.69, p=0.002), and ¹¹C-UCB-J binding in putamen correlated with UHDRS motor score (r_p= -0.82, p<0.001) and SDMT (r_p=0.69, p=0.001).

Conclusion: ¹¹C-UCB-J PET revealed extensive loss of SV2A in early HD, suggesting widespread synaptic disconnection. SV2A loss in the striatum correlated with motor and cognitive functioning. ¹¹C-UCB-J PET is more sensitive than ¹⁸F-FDG PET for detection of extrastriatal changes in early HD.

References: [1] DiProspero NA et al. (2004) Early changes in Huntington’s disease patient brains involve alterations in cytoskeletal and synaptic elements. J Neurocytol 33:517-533. [2] Niccolini F, Pagano G, Fusar-Poli P, Wood A, Mrzljak L, Sampaio et al 2017, ‘Striatal molecular alterations in HD gene carriers: a systematic review and meta-analysis of PET studie’, J Neurol Neurosurg Psychiatry, 89(2), 185-196. [3] Finnema SJ, Nabulsi NB, Eid T, Detyniecki K, Lin SF, Chen MK, et al 2016, ‘Imaging synaptic density in the living human brain’, Sci Transl Med, 8, 348ra96.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/widespread-loss-of-presynaptic-terminal-marker-sv2a-in-early-huntingtons-disease/