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

Abstract

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. <b>Methods:</b> CB₁R binding was measured with ¹⁸F-MK-9470 (<i>N</i>-[(2<i>S,</i>3<i>S</i>)-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 ¹⁸F-MK-9470 were corrected for partial-volume effect. <b>Results:</b> 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, <i>P</i> = 0.01-0.005). The PBA-HD scores inversely correlated with CB₁R binding in prefrontal regions and cingulate cortex in pre-HD (range: <i>r</i> = -0.64 to -0.72; <i>P</i> = 0.01-0.008). <b>Conclusion:</b> 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.