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, 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 premanifest HD mutation carriers (preHD). Methods: CB1R binding was measured with ¹⁸F-MK-9470 PET in 15 preHD subjects (8M/7F; age 39.3±9.9 years), 15 gene-negative controls from HD families (9M/6F; age 37.0±10.6 years) and 12 community controls (6M/6F; age 39.9±15.1 years). All subjects also underwent extensive assessment of motor and cognitive function, as well as a behavioral test battery including the Problem Behaviour Assessment for HD (PBA-HD), and MRI. Parametric binding images of ¹⁸F-MK-9470 were corrected for partial volume effect. Results: There was no difference in CB₁R binding, grey 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 (CON). Compared to CON, preHD 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 preHD (range r = -0.64 – -0.72; range 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 premanifest HD and suggest new therapeutic avenues.