F017 Peripheral inflammation may drive behavioral symptoms in Huntington’s disease

<h3>Background</h3> Peripheral inflammation has long been hypothesized to contribute to Huntington’s disease (HD) pathophysiology. Increased peripheral inflammation has been implicated in ‘sickness behavior,’ a set of adaptive behaviors in response to an infection or a traumatic lesion that results in changes in mood/motivation, appetite, and sleep. Psychiatric and/or behavioral symptoms are essential components of HD, yet their underlying mechanisms are not fully understood. <h3>Aims</h3> To determine whether peripheral inflammation is associated with behavioral symptoms in HD. <h3>Methods</h3> 39 HD gene expansion carriers (HDGECs, 21 manifest, and 18 premanifest) underwent clinical evaluation that included motor (UHDRS), cognitive (SDMT), and behavioral (PBA-s) assessments. Peripheral blood was drawn, and plasma levels of the inflammatory cytokines [interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL-13, interferon (IFN)-γ and tumor necrosis factor (TNF)-α] were simultaneously assessed by bead-based immunoassay. We performed principal component analysis (PCA) and k-means clustering with a predetermined optimal number of clusters (elbow method) to identify subgroups of HDGECs based on their levels of cytokines and PBA-s scores. <h3>Results</h3> We identified two clusters (clusters 1 and 2 – see figure 1) that clearly distinguished individuals based on their levels of circulating inflammatory cytokines and behavioral symptoms. These clusters did not differ regarding age, sex, CAG repeats, disease stage (premanifest vs. manifest), or clinical scores (UHDRS, SDMT). Conversely, they did show significant differences in all PBA-s domains (depression, irritability/aggression, apathy, psychosis, and executive function, table 1). <h3>Conclusions</h3> Our findings indicate that peripheral inflammation is associated with behavioral symptoms in HD, akin to cytokine-induced ‘sickness behavior’.