Synaptic Damage and Its Clinical Correlates in People With Early Huntington Disease A PET Study

Background and Objectives Synaptic damage has been proposed to play a major role in the pathophysiology of Huntington disease (HD), but in vivo evidence in humans is lacking. We performed a PET imaging study to assess synaptic damage and its clinical correlates in early HD in vivo. Methods In this cross-sectional study, premanifest and early manifest (Shoulson-Fahn stage 1 and 2) HD mutation carriers and age- and sex-matched healthy controls underwent clinical assessment of motor and nonmotor manifestations and time-of-flight PET with C-11-UCB-J, a radioligand targeting the ubiquitous presynaptic terminal marker synaptic vesicle protein 2A (SV2A). We also performed F-18-fluorodeoxyglucose (F-18-FDG)-PET in all participants because regional cerebral glucose consumption is thought to largely reflect synaptic activity. Volumes of interest were delineated on the basis of individual 3-dimensional T1 MRI. Standardized uptake value ratio-1 images were calculated for C-11-UCB-J with the centrum semiovale as reference region. F-18-FDG-PET activity was normalized to the pons. All PET data were corrected for partial volume effects. Volume of interest- and voxel-based analyses were performed. Correlations between clinical scores and C-11-UCB-J PET data were calculated. Results Eighteen HD mutation carriers (age 51.4 +/- 11.6 years; 6 female; 7 premanifest, 11 early manifest) and 15 healthy controls (age 52.3 +/- 3.5 years; 4 female) were included. In the HD group, significant loss of SV2A binding was found in putamen, caudate, pallidum, cerebellum, parietal, and temporal and frontal cortex, whereas reduced F-18-FDG uptake was restricted to caudate and putamen. In the premanifest subgroup, C-11-UCB-J and F-18-FDG-PET showed significant reductions in putamen and caudate only. In the total HD group, SV2A loss in the putamen correlated with motor impairment. Discussion Our data reveal loss of presynaptic terminal integrity in early HD, which begins in the striatum in the premanifest phase, spreads extensively to extrastriatal regions in the early manifest phase, and correlates with motor impairment. C-11-UCB-J PET is more sensitive than F-18-FDG-PET for detection of extrastriatal changes in early HD. Classification of Evidence This study provides Class III evidence that C-11-UCB-J PET accurately discriminates individuals HD from normal controls.

Automated summary

The study found synaptic damage in early HD, starting in the striatum in the premanifest phase and spreading extensively to extrastriatal regions related to motor impairment in the early manifest phase. C-11-UCB-J PET is more sensitive than F-18-FDG-PET for detecting extrastriatal changes in early HD.