CB1R PET in premanifest and manifest Huntington’s disease is related to disease onset and disease burden

Objectives Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder causing a triad of motor, cognitive and psychiatric symptoms. Several studies have suggested a downregulation of the cerebral cannabinoid type 1 receptor (CB1R) in HD, even in early disease stages. No in vivo human studies in premanifest carriers of the HD mutation gene (preHD) has been reported so far. Our aim was to assess CB1R levels in the brains of both preHD subjects and manifest HD patients, in comparison to healthy controls, using [18F]MK-9470 PET. Secondly, the relation to disease onset and disease load was investigated.

Methods 15 preHD subjects (8M / 7F; age 39.3 ± 9.9 y; number of CAG repeats in the HTT gene [CAGn] range 40-46), 19 manifest HD patients (HD; 7M / 12F; age 51.7 ± 10.2 y, CAGn range 40-50, disease duration range 0.5-13.6 y) and 36 healthy controls, age-matched to both groups, community and sibling CON_preHD (n = 27; 15M / 12F; age 38.2 ± 12.6 y) and community HD controls (CON_HD; n = 9; 4M / 5F; age 55.7 ± 10.7 y), underwent CB1R [18F]MK-9470 PET. Parametric images of [18F]MK-9470 modified standardized uptake value (mSUV), reflecting CB1R availability, were corrected for partial volume effect and analyzed using both voxel- and VOI-based analyses with post-hoc tests.

Results There was no difference in CB1R availability between community and sibling CON_preHD. Compared to CON_preHD, preHD subjects showed a small global reduction (-6.1 ± 0.4%) in CB1R availability, with a trend of decreased CB1R availability in the ventromedial prefrontal cortex (-9%, p = 0.08). Levels in manifest HD patients were strongly reduced across all the brain regions (in average -21.9 ± 3.8% and -24.8 ± 2.4% compared to preHD and CON_HD respectively; p < 0.0005 in all regions; see Figure A). The predicted time to disease onset correlated positively with CB1R levels in the caudate head in preHD (r = 0.69, p = 0.005). In addition, the disease burden ([CAGn - 35.5] x age) was negatively correlated with CB1R levels in the caudate nucleus (r = -0.65, p < 0.001; see Figure B) and prefrontal cortex (r = -0.54, p = 0.001) over both disease stages.

Conclusions A decrease in CB1R availability already starts in the premanifest phase of HD and related to time to disease onset and to the disease burden. This study supports the progressive global redution in CB1R by mutant hungtintin and the relevance of CB1R imaging as a marker of functional disease progression.

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