Background Apathy and depression are extremely common features of Huntington’s disease (HD) identifiable years before motor-based clinical onset. However, little is known about the underlying neural mechanisms subserving their clinical expression.

Objectives Given the importance of defining early biomarkers of disease progression and to clarify the pathophysiological substrates of these features, we performed 18-FDG PET/CT in a sample of n = 11 pre-manifested (preHD) individuals with/without affective symptoms.

Methods Based on the PBA-s, participants were grouped as with significant affective symptoms (PBA-s apathy and/or depression score ≥2; PreHD-Af) and without affective symptoms (PreHD-nAf). Motor, functional and cognitive assessments were performed. PET/CT was done 50 min after 18-FDG injection. T-test comparisons between groups and regression analysis separating apathy and depression scores were done using standard SPM8 techniques.

Results No differences were found between groups comparing for mean CAG length=42.4 ± 3.8, age=42.5 ± 12.1, education =13.8 ± 3.8, UHDRS-motor=1.64 ± 1.6, TFC=12.9 ± 0.3, cognition=101 ± 14.3 or disease burden=296.7 ± 127. Group analysis showed no significant differences in caudate nuclei, but significant hypometabolism in areas of the prefrontal (PFC) and temporal cortex involved in emotional resonance, emotion comprehension, and social interaction. PreHD-Af patients exhibited hypometabolism in the right posterior fronto-median cortex (p-FMC; BA8), right frontopolar PFC (BA10), and right inferior temporal gyrus (BA20) (uncorrected p < 0.004). Apathy scores significantly correlated with hypometabolism in the dorsolateral PFC (right-BA46), right frontopolar PFC, and left posterior insula (BA13), while depressive scores related to hypometabolism in the right medial PFC (BA 9), right occipitotemporal cortex (BA37), bilateral temporal pole (BA38), and bilateral associative parietal cortex (BA40) (uncorrected p < 0.005).

Discussion PreHD patients already exhibit a pattern of hypometabolism involving areas that play a major role in the processing of inner emotions and socially relevant signals. Apathy appeared related to PFC structures subserving emotion control and comprehension, while depressive symptoms extended to parieto-temporal regions linked to emotional processing.