Positron emission tomography (PET) imaging with 11C-UCB-J, a PET radioligand for synaptic vesicle protein 2A (SV2A), can detect extrastriatal changes in early Huntington disease (HD) and the tracer is more sensitive than 18F-fluorodeoxy glucose (18F-FDG) PET, according to study results published in Neurology.

Prior studies have suggested that synaptic dysfunction has a key role in the pathophysiology of HD, but data in humans are limited. The objective of the current study was to characterize synaptic damage in early HD using PET imaging and to assess its clinical correlates.

The cross-sectional study included 18 HD mutation carriers (mean age, 51.4 years; 6 women) and 15 healthy control individuals (mean age, 52.3 years; 4 women) matched for age and gender. All participants underwent a comprehensive clinical assessment of motor and nonmotor manifestations, as well as a 30-minute 11C-UCB-J time-of-flight PET-CT scan and 18F-FDG PET.


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Imaging with 11C-UCB-J showed significant loss of SV2A binding in the HD group in putamen (mean decrease, -28%; P <.001), caudate (-25%; P <.001), pallidum (-24%; P <.001), cerebellum (-11%;  P =.002), parietal cortex (-9%; P =.002), temporal cortex (-9%; P =.002) and frontal cortex (-8%; P =.004), as well as in whole gray matter (-9%; P =.002).

However, using 18F-FDG radioligand, reduced uptake was restricted to caudate (mean difference, -31%; P <.001) and putamen (-31%; P <.001).

There was a significant positive correlation between 11C-UCB-J binding and volume of putamen in HD mutation carriers. In addition, there was a significant correlation between SV2A binding and glucose metabolism in putamen and caudate, but not in other brain regions.

In the total HD group, SV2A loss in the putamen correlated with motor impairment, according to Unified Huntington’s Disease Rating Scale motor assessment.

Voxel-based analysis showed widespread decrease of 11C-UCB-J binding in HD, most obviously bilaterally in striatum and thalamus and in right superior and middle occipital gyrus. The striatum was the only region showing significant SV2A loss in patient premanifest HD, suggesting that SV2A loss in HD may first occur in the striatum.

The main limitation of the current study was the small sample size and limited power.

“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. 11C-UCB-J PET is more sensitive than 18F-FDG PET for detection of extrastriatal changes in early HD,” concluded the researchers.

Reference

Delva A, Michiels L, Koole M, Van Laere K, Vandenberghe W. Synaptic damage and its clinical correlates in people with early Huntington disease: a PET study. Neurology. Published online October 18, 2021. doi: 10.1212/WNL.0000000000012969