Behavioral Symptoms in Premanifest Huntington Disease Correlate with Reduced Frontal CB1R Levels

Many Huntington disease (HD) mutation carriers already have cognitive and psychiatric symptoms in the premanifest (premotor) phase of the disease (pre-HD), but the molecular underpinnings of these symptoms are not well understood. Previous work has shown reduced availability of the cerebral type 1 cannabinoid receptor (CB1R) in manifest HD. Here, we investigated whether CB1R binding is related to cognitive and psychiatric symptoms in pre-HD mutation carriers. Methods: CB1R binding was measured with F-18-MK-9470 (N-[(2S,3S)-3-(3-cyanophenyl)-4-(4-ethoxyphenyl)butan-2-yl]-2-methyl-2-(5-methylpyridin-2-yl) oxypropanamide) PET in 15 pre-HD subjects (8 men, 7 women; age, 39.3 +/- 9.9 y), 15 gene-negative controls from HD families (9 men, 6 women; age, 37.0 +/- 10.6 y), and 12 community controls (6 men and 6 women; age, 39.9 +/- 15.1 y). All subjects also underwent extensive assessment of motor and cognitive function, as well as a behavioral test battery including the Problem Behavior Assessment for HD (PBA-HD), and MRI. Parametric binding images of F-18-MK-9470 were corrected for partial-volume effect. Results: There was no difference in CB1R binding, gray matter volume, cognitive function, or psychiatric scores between gene-negative controls from HD families and community controls, which were therefore pooled to one control group. Compared with controls, pre-HD subjects showed striatal atrophy, a decrease in CB1R binding in the prefrontal cortex, and higher PBA-HD scores on depression, apathy, and irritability (range, P = 0.01-0.005). The PBA-HD scores inversely correlated with CB1R binding in prefrontal regions and cingulate cortex in pre-HD (range: r = -0.64 to -0.72; P = 0.01-0.008). Conclusion: The association between behavioral symptoms and reduced prefrontal CB1R levels may provide new insight into the molecular basis of neuropsychiatric symptoms in pre-HD and suggest new therapeutic avenues.