## 4 Discussion  
Few studies have assessed the burden of IHD and HD-CPs relative to those without HD (i.e., GP) or to those with a different progressive neurological disease. Here, we examined the clinical and humanistic burdens of HD in this broader context by comparing to age- and/or sex-adjusted GP and PD cohorts. Our data support the evidence of a high burden for IHD and their care partners relative to GP (but similar burden as PD) and provide evidence of unique and common burdens observed among HD and PD cohorts. Consistent with prior studies [35; 36; 37; 38], IHD reported significantly poorer HRQoL than individuals without HD (i.e., GP), with lower scores being observed on both the EQ-5D and EQ-VAS. This result was not surprising, given the known clinical and symptomatic features of HD and their progressive role in disrupting one's independence, capacity to work, and ability to fulfill routine activities of daily life [27]. Indeed, roughly 88% of our IHD cohort identified as being in the Early- to Mid-Stage of HD progression, with the most common symptoms being involuntary movements/spasms and cognitive issues. This finding is consistent with prior work implicating cognitive and motor impairment as some of the most impactful symptoms reported by patients and care partners [22], and as significant moderators of functional ability and HRQoL [14; 39]. In addition to cognitive impairment, researchers have noted a substantial role of mental health and mood dysregulation in HD [5]. Prior studies have found depression and anxiety to be significant determinants of HRQoL in HD [15; 37; 40] and HD-CP [40]; in fact, anxiety and depression appear to be the most severely altered dimensions on the EQ-5D among those with HD [35]. Consistent with these results, IHD in this study exhibited approximately 2-fold higher prevalence of mental health-related disorders and more severe depression (as assessed by the PHQ-9) than GP--notably, the IHD cohort exceeded the diagnostic cut-off (PHQ-9 score of 10+) for major depressive disorder (PHQ-9: IHD = 11.6 vs. GP = 5.9) [29]. HD-CP also exhibited greater comorbid anxiety and depression, and more severe depression (as calculated by PHQ-9 scores) than GP-CP. These clinical findings are supported by respondents' survey data, with half of HD-CP reporting feeling lonely/isolated and experiencing extreme impacts on emotional health. Similarly, over half of IHD report difficulty maintaining relationships, remaining independent, and being fearful of their eventual mental and physical decline. All these features may contribute to the greater degree of anxiety and depression observed among HD cohorts in this study. Notably, there were a few key differences observed among IHD and HD-CP cohorts relative to IPD and PD-CP cohorts in this study--HD cohorts were roughly twice as likely to report having comorbid anxiety (IHD = 51.2% vs. IPD = 28.8%; HD-CP = 52.5% vs. PD-CP = 28.6%) and depression (HD-CP = 65.0% vs. PD-CP = 29.9%) than PD cohorts, despite reporting comparable levels of HRQoL (EQ-5D measures, NS). These results are consistent with a recent study that reported a higher incidence of anxiety and major depressive disorder in IHD than IPD, as well as the general population [41]. Given that both HD and PD are progressive neurological disorders with similar symptomatology, it is interesting to consider whether HD is specifically associated with greater mood dysregulation than PD, or whether this is a symptom of design artifact (e.g., sociodemographic differences that could contribute to underlying stress, e.g., financial stability). For example, IHD were significantly younger and tended to earn lower wages than IPD in this study--factors which could exacerbate stress in the face of financial concerns. Indeed, roughly three-quarters of our IHD cohort reported that their symptoms caused them to change jobs or quit working. The majority of HD-CP similarly noted that their work life had suffered because of caregiving and that they had difficulty saving money, in line with previous findings [42].