Identifying and Mapping Meaningful Cognitive Symptoms and their Impacts in Huntington’s Disease

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Little is known about what symptoms are considered personally meaningful to people with HD and how these symptoms affect everyday life. This study aimed to identify personally meaningful cognitive symptoms in people with HD and map these symptoms to their everyday impacts. We conducted semi-structured symptom mapping interviews with 18 people with HD before and after clinical motor diagnosis. Participants rated their symptoms from “Not important” to “Very or Most Important” and as “Not Present” to “Most or Very Bothersome”. Interview transcripts were analysed using Reflexive Thematic Analysis (RTA) to identify key impacts of cognitive symptoms and symptom maps were collated to characterise the frequency of important and bothersome symptoms. Altered problem solving was most frequently rated as important whereas memory changes were most frequently rated as bothersome. We identified three themes and eight subthemes from interviews which elucidated how participants feel cognitive symptoms are important for their everyday lives. Specifically, changes in cognition affected: (1) everyday activities; (2) sense of wellbeing; and (3) personal relationships. Overall, we found that cognitive symptoms were both important and bothersome from the perspective of people living with HD. Health sciences/Diseases Health sciences/Health care Health sciences/Neurology Biological sciences/Neuroscience Biological sciences/Psychology Social science/Psychology Health sciences/Signs and symptoms Cognition Huntington’s endpoints lived experience Figures Figure 1 Figure 2 Introduction The Patient Focused Drug Development (PFDD) guidance series released by the U.S. Food and Drug Administration (FDA) emphasises the importance of integrating patient experience data at all stages of clinical trial design [ 1 ]. Patient experience data provides information about a patients’ experiences with a disease or condition, including its symptoms, the impact to function and quality of life, and patient preferences for priorities in clinical trials [ 1 ] The selection and development of efficacy endpoints is an aspect of clinical trial design where patient experience data is viewed as especially important. Clinical trial endpoints must reflect relevant ‘Concepts of Interest’, which are signs, symptoms or clinical events that are considered clinically meaningful to patients [ 2 ]. Using the guidance offered in the FDA’s PFDD series, we and others are working to identify disease symptoms and impacts that are meaningful to patients and designing clinical trials efficacy endpoints to align with patient priorities and values. For example, the meaningfulness of particular disease symptoms has been studied in Alzheimer’s disease (AD) [ 3 – 7 ] and Parkinson’s disease (PD) [ 8 – 10 ] using a mix of qualitative and quantitative methodologies (e.g., interviews, surveys). These studies are instrumental in shaping patient-focused clinical research by identifying patient priorities for clinical trials and clinically meaningful concepts of interest to inform endpoint strategies. Patient-experience data is also of increasing interest for informing clinical trial design in Huntington’s disease (HD), which is an autosomal dominant neurodegenerative disorder characterised by motor dysfunction, cognitive decline, and neuropsychiatric symptoms [ 13 ]. To date, HD patient experience data have been described in a white paper from the FDA as part of their ‘Voice of the Patient’ series, as well as in several additional published studies [ 11 – 14 ]. All studies described non-motor symptoms, such as cognitive and executive dysfunction, as the most bothersome disease features with greatest impact from the perspective of people with HD and caregivers, in turn identifying cognition as a high priority target for the development of new treatments. Cognitive decline in HD emerges early in the disease course [ 15 – 17 ] and is characterised by gradual declines in processing and psychomotor speed, memory retrieval, attention, and executive function [ 18 – 20 ]. Cognitive deficits contribute to difficulties in everyday activities, including domestic tasks, work activities, driving, communication, and relationships [ 21 , 22 ], and are associated with declining quality of life [ 22 , 24 ]. Despite people with HD and their caregivers assigning high significance to cognitive decline in their experience of HD, systematic research has not yet explored the patient perspective regarding the relevance of particular cognitive symptoms, nor the impact of cognitive decline on daily functioning. Identifying cognitive concepts of interest that are ‘clinically meaningful’ is an essential step for informing targeted treatment development, and for designing meaningful cognitive endpoint measures for clinical trials [ 25 ]. The FDA defines ‘clinically meaningful’ concepts of interest as symptoms that have a recognisable impact to everyday function, quality of life, or survival [ 25 ]. In this study we aimed to build on previous work collecting patient-experience data in HD and identify cognitive symptoms that, from the patient perspective, are important and bothersome, and to map these symptoms to their everyday impacts. We used a symptom mapping approach, including rating scales, semi-structured interviews, and qualitative analysis, adapted from the work of Mammen et al. in PD [ 9 , 26 ]. Methodology Study Design We used a cross-sectional qualitative design using semi-structured interviews and symptom mapping. The findings from this study are part of a larger study design that included completing the Huntington’s Disease Cognitive Assessment Battery (HD-CAB) [ 27 ] and a second interview exploring perceptions around cognitive testing. This study was approved by the Monash University Human Research Ethics Committee (MUHREC ID: 36930) and all research was performed in accordance with relevant guidelines and regulations. Study procedures were in accordance with the Declaration of Helsinki. Participants We recruited 18 CAG expansion carriers (CAG ≥ 38) experiencing either subjective or overt signs and symptoms of HD (see Table 1 for participant characteristics). Participants were recruited from various sources, including HD research volunteer databases, social media, and local specialist clinics. We intentionally kept inclusion and exclusion criteria broad to include a clinically varied sample. Participants were eligible for the study if they had undergone genetic or predictive testing, were experiencing subjective or overt signs and symptoms of HD and scored between 7 and 13 on the Unified Huntington’s Disease Rating Scale (UHDRS) Total Functional Capacity (TFC) scale [ 28 ]. Exclusion criteria included neurological disorders except for HD and neurodevelopmental disorders, history of acquired brain injury, current excessive alcohol or drug use, and self-reported mental health disorders that may reasonably make it difficult to participate in the interview. We staged participants’ disease progression for demographic purposes using the Shoulson-Fahn Staging System and the Huntington’s Disease Integrated Staging System (HD-ISS) [ 29 , 30 ]. The Shoulson-Fahn Staging system uses ratings on the TFC to stage functional impairment in HD across five stages ranging from Stage 1 (TFC = 11–13), Stage 2 (TFC = 7–10), Stage 3 (TFC = 3–6), Stage 4 (TFC = 1–2) and Stage 5 (TFC = 0) [ 30 ]. The HD-ISS uses biological and clinical disease indicators to stage people with HD across four stages, from Stage 0 (CAG ≥ 40, no pathological or clinical changes), Stage 1 (detectable pathological changes), Stage 2 (detectable cognitive or motor changes), and Stage 3 (detectable function changes) [ 29 ]. Twenty people with HD originally agreed to participate in the study. Two participants withdrew prior to the study session due to difficulty finding time to complete the study session or ceasing communication with the research team prior to their scheduled session. Table 1 Participant characteristics. Mean age in years (SD) 54.94 (13.39) Range 32–72 % Female 50% Mean TFC score (SD) 10.56 (2.36) Range 7–13 Mean CAG expansion length (SD) 42.23 (3.27) Range 38–52 Mean years of education (SD) 14.62 (1.82) Range 11–17 TFC Stages n Stage 1 (11–13) 10 n Stage 2 (7–10) 8 HD-ISS n Stage 0–1 6 n Stage 2 0 n Stage 3 12 Note : TFC = Total Functional Capacity; CAG = cytosine-adenine-guanine; HD-ISS = Huntington’s Disease Integrated Staging System. HD-ISS Stage 2 is based on cut-offs derived from the Symbol Digit Modalities Task (SDMT) and/or the UHDRS Total Motor Scale (TMS); we only had access to participant performance on the SDMT. Some participants staged as HD-ISS 0–1 had received a motor diagnosis. Measures Demographic questionnaire We administered a brief demographic questionnaire over the phone when screening participants. We obtained information related to age, gender, education, occupational history, medical history, psychiatric history, and drug and alcohol history, and questions related to HD history (e.g., CAG expansion length, year of diagnosis if known). Total Functional Capacity (TFC) scale We administered the TFC to estimate disease severity. The TFC scale is a clinician-rated subscale of the UHDRS and assesses functional capacity to independently carry out activities such as work, manage finances, personal grooming, hygiene, and the extent to which they need caregiving [ 28 ]. Participant scores can range from 0–13, with higher scores indicating better functional capacity and in turn, lesser disease severity. University of California San Diego Huntington’s Disease Behaviour Questionnaire (UCSD HDBQ) Cognitive symptoms can be abstract and difficult for people to observe and self-identify; therefore, we used the UCSD HDBQ as a symptom checklist to help participants generate and describe symptoms that they were experiencing. The UCSD HDBQ is a self-report questionnaire which captures 30 cognitive and behavioural symptoms in HD [ 31 ]. Participants are asked to rate, using a four-point Likert scale ranging from Completely Disagree to Completely Agree , the extent to which they agree that they have experienced a change in each of the 30 symptoms over past 12 months. Procedure We adapted procedures from a previous study conducted in PD [ 9 ]. Interested participants were screened over the phone and invited to attend an in-person study session either at the Monash University Turner Clinics or at their own home. All participants provided written informed consent prior to participating in study activities. Participants completed the UCSD HDBQ prior to the semi-structured interview. CR (a PhD candidate in clinical neuropsychology) conducted all interview sessions. Interviews aimed to explore participants’ experience with cognitive symptoms of HD and how these changes have been important for their everyday lives. Interviews ranged from 37 minutes to 127 minutes in length, which included a second cognitive interview, and all interviews were recorded and transcribed verbatim. The semi-structured interviews followed an interview guide (Table 2 ), and we used additional prompts as needed (e.g., “can you tell me more about that?” “Can you tell me more about why you gave this rating?” ). We refined the interview guide and methodology early in data collection to address any issues that arose. We started interviews by discussing symptoms that participants reported had worsened over the past 12 months on the UCSD HDBQ. Next, we prompted participants for domains of cognitive function that are commonly impacted in HD, including memory, psychomotor rhythm, planning, problem solving, recognising emotions, processing speed, and switching attention. We asked participants about any other symptoms they felt were important to discuss, including symptoms they were not yet experiencing but believed would be important in the future. We completed symptom mapping using XMind (version 24.04.10291) to create a detailed map of the participant’s experience with their HD symptoms. Symptom mapping is a technique used to delineate meaningful symptoms and their impacts from the patient perspective [ 26 , 32 – 34 ]. We completed symptom mapping collaboratively with the participant observing and validating data entry throughout the interview (see an example of a completed symptom map in the Supplementary Materials, Appendix A , Fig. 1 A). Symptoms were organised in symptom maps from Not Important, Somewhat Important and Very or Most Important , and nodes were attached to each symptom detailing how bothersome participants believed the symptom was to everyday life, ranging from 0. No Issues Present; 1. Not Very Bothersome; 2. Somewhat Bothersome ; 3. Very or Most Bothersome . Each participant was provided with a $ 40 gift card after completing study activities. Table 2 Interview schedule for symptom mapping interview. Topic Questions 1. Impact of current cognitive symptoms to everyday life. 1. You’ve indicated that you have experienced a change in [cognitive symptom]. Can you tell me what that looks like for you? 2. How important would you rate this change from not at all, somewhat, to very important to you? 3. How bothersome or impactful has this change been to everyday life, from 0 (not present); 1 (not very bothersome); 2 (somewhat bothersome); or 3 (very or most bothersome)? 4. How does change in [cognitive symptom] impact your everyday life? 2. Eliciting any spontaneously reported symptoms. 1. Are there any other changes in how you think or in mental abilities which we have not spoken about that you think might be due to HD? [if YES, return to topic 1]. 3. Eliciting symptoms not currently experienced. 1. There might be some changes in thinking or in mental abilities which you have not noticed but can sometimes happen in HD. When you think about these kinds of changes, are there any that you are more concerned about? [if YES, return to topic 1]. 4. Final questions. 1. Is there anything else about your experience with cognitive symptoms in HD that you’d like to share? 2. How did you find the symptom mapping process? Analysis CR analysed interview transcripts using Reflexive Thematic Analysis (RTA) [ 35 ]. Data analysis was based on a primarily deductive approach and was situated within a critical realist paradigm. Transcripts were reviewed for accuracy to ensure they were transcribed verbatim, and annotations were made highlighting interesting observations. CR conducted initial coding of all interview transcripts, then grouped related codes to identify preliminary themes. Codes and themes were reviewed and refined iteratively throughout the course of data analysis, with themes finalised after all transcripts had been analysed. We used a mix of Nvivo (version 14.23.4), and Excel and Word (versions 16.94) to complete our data analysis. CR kept a reflexivity journal throughout data analysis and engaged in discussion with other members of the research team as needed to enhance understanding of codes or themes, and to enhance rigour [ 36 ]. We analysed the symptom maps with content coding using Excel (version 16.94) to code symptom type, frequency, importance, and bothersomeness of symptoms and their impacts. We also used interview transcripts to code any additional data that was not originally included into the symptom map. We classified symptoms as important if they were rated as either Somewhat Important or Very or Most Important and classified symptoms as bothersome to everyday life if they were rated as bothersome to any degree, including Not Very Bothersome , Somewhat Bothersome , or Very or Most Bothersome . Coding was completed by CR with input from members of the research team as needed. Results The frequency that symptoms were rated as important ranged from 0 to 94.44% and the frequency that symptoms were rated as bothersome ranged from 0 to 83.33%. Symptoms were often rated as important by participants, even if not currently bothersome. Most Important HD Cognitive Symptoms Participants most frequently rated problem solving as important (94.44%), with 61.11% of participants rating it as Most or Very Important and 33.33% rating it as Somewhat Important. After problem solving, memory was next most frequently rated as important (88.89%), followed by processing speed (83.33%). These ratings were independent of how bothersome symptoms were rated. Figure 1 shows the frequency of importance ratings for each symptom. Most Bothersome HD Cognitive Symptoms Participants most frequently rated memory as an actively bothersome symptom (83.33%) with 50% reporting it as Most or Very Bothersome . Processing speed, time to respond , and shifting attention were each rated as bothersome by 72.22% of participants. Of note, processing speed and taking more time to respond were often conceptualised by participants as similar constructs. Concentration was bothersome to 66.67% of the sample. These ratings were independent of how important symptoms were rated. Figure 2 shows the frequency of bothersome ratings for each symptom. We identified three themes and eight subthemes from interviews (see Table 3 ). Themes and subthemes were focused on participant perceptions of how different cognitive changes affected their everyday life and why they thought these changes were important. Tables 4 shows the percentage of the sample that were represented by each theme and subtheme, as well as the symptom that was most frequently mapped to each theme. Additional quotes are presented in the Supplementary Materials (Appendix B , Table 1 B). Theme 1: Changes in cognition affect my everyday activities The participants in our study were at different stages of disease progression and were therefore experiencing different levels of functional impairment. Given the progressive nature of HD, some participants detailed specific ways that cognitive changes had already affected their functional abilities whereas others discussed how they anticipated future symptoms would affect their lives. This theme also captured participants' current reliance on cognitive skills for daily activities, suggesting that deterioration in these skills would threaten their ability to engage in normal tasks. Subtheme 1.1: Changes in cognition affect my ability to work . Participants discussed how their cognitive symptoms contributed to difficulties with work. The participants in our sample had varied employment situations: some participants were still working full time, whereas others had transitioned to part-time or supported work, or had ceased work due to HD symptoms. Several participants reported that they were retired from paid employment and instead were focused on volunteering. P14: “Because it [memory changes] meant that I couldn’t do a particular quality of work. So, I’m now on income protection.” - memory Subtheme 1.2: Changes in cognition affect my leisure activities Many participants discussed how cognitive decline had affected their leisure activities, such as playing or watching sport, playing instruments, dancing, collecting, or otherwise spending time with their friends and family. P12: “… it’s annoying. I play guitar and now can’t keep the beat…Yeah, in a band…with the kids and that.” - psychomotor rhythm Some participants also highlighted that while they were still capable of doing their hobbies, difficulties with increased fatigue and amotivation precluded them from completing those activities. P6: “So, there’s a whole list of the things I used to do, activities that I don’t do anymore. I don’t play golf, … I used to work on a family tree…collected coins, I pretty much haven’t done any of those things.” – amotivation/loss of interest Subtheme 1.3: Changes in cognition affect my ability to drive Like other areas of function, our sample included participants who experienced different levels of driving impairment. Some participants reported that they were no longer driving or had restrictions on their licence due to their HD, while others continued to drive unrestricted. P5: “I’ll be driving the car and the missus will want a conversation as you’re driving through the barrel of traffic… “yeah hang on, I need to concentrate on the road here”.” – switching attention Two participants lived outside of the metropolitan area and highlighted that being able to drive was important to them for their independence. P18: “This place ain’t the easiest place to get a bus and I hate public transport. So, driving a car is beautiful.” Subtheme 1.4: Changes in cognition affect my ability to do domestic activities Participants discussed the impact of cognitive changes for their ability to complete domestic activities, such as cleaning, cooking, or doing the gardening. Some participants described needing to use adaptations to complete tasks, whereas others noted that they no longer can complete regular activities. Several participants reported that they received funding through government schemes to help manage some of their domestic chores. P15: “I can’t multitask, that’s impossible…when I’m cooking. I have to do one thing at a time…so, it means preparing the meals, that’s just preparing meals. If I do the washing, I just do the washing. If I do the cleaning, I just do the cleaning.” – switching attention One participant stated that he had the resources to outsource certain tasks, which mitigated the impact of cognitive changes on his day-to-day life. P17: “…I don’t have to do [the gardens] anymore. I can afford to have someone do it. And I don’t really like doing it.” – avoiding complex activities Subtheme 1.5: Changes in cognition affect my finances Cognitive symptoms were also viewed as important for financial management, including paying bills on time, impulsively shopping, or acquiring debt. Several participants stated they were no longer primarily in charge of the finances, with their spouse or other family members taking over financial management tasks. One participant reported that they had recently lost control of their finances and were required to appoint an alternate financial decision maker. P4: “Not all the time, just on the odd occasion it gets a bit, yeah…I sorta have regret…on what I’ve done…. Luckily not in crazy amounts of debt.” – impulsivity P18: “So, she thinks I’m not able to manage my finances…” – avoiding complex activities Subtheme 1.6: Changes in cognition affect my ability to interact and socialise Almost all participants stated that cognitive symptoms had affected their ability to interact and socialise with others. Participants described how they have more difficulty engaging in conversation due to taking longer to process and respond to information and highlighted that they would sometimes act inappropriately in social settings. These difficulties often made socialising more anxiety inducing, and some participants noted that they avoided interacting as a result. P16: “But [laugh] [I] don’t spit it out, don’t think of the answer…, I’ve created a, like, four-second gap. He’s looking at me, and I’m looking at him …I’m like, double checking. By the time I’ve gone from all that in me head, …it’s like four seconds, five seconds, just to say yes or no.” – processing speed P17: “…hard right turns in a conversation can sometimes really throw me and I find myself just dipping out.” – switching attention Theme 2: Changes in cognition affect my wellbeing Participants discussed how their cognitive symptoms had a negative effect on their wellbeing. Cognitive symptoms were described as causing participants to feel frustrated, annoyed, depressed, embarrassed, stressed or misunderstood. Some participants also highlighted how cognitive changes affected their self-esteem or exacerbated existing mental health issues, highlighting the interconnected nature of HD symptoms. Participants reflected on their current wellbeing and how cognitive and behavioural symptoms would affect their wellbeing as the disease progressed. P1: “Well, I probably would get more frustrated …the stress levels would go up because I couldn’t deal with whatever the situation was that I needed to deal with.” – problem solving P9: “It’s things that I’m losing, that I had. That is frustrating. ... I’ve always been able to concentrate, and I was a bookkeeper for 30 odd years.” – concentration Some participants also discussed how the stigma they experienced because of their symptoms contributed to worse wellbeing, rather than the symptoms themselves. For example, two participants reflected on how they were often perceived as being inebriated due to communication, language, and motor changes. P18: “Oh, yeah, important not, for people not to judge me, that I’m not drunk.” P16: “Someone’s like, “oh c’mon mate, you’ve already had enough to drink.” When I’ve had like, one drink.” Theme 3: Changes in cognition affect my relationships Many participants discussed how their cognitive symptoms had changed the dynamics of their close relationships, often putting greater burden on their partners and family members. Conversely, participants also reflected on how cognitive symptoms made them more vulnerable in their relationships as they lost personal autonomy. Some noted that they had lost valued connections because of their HD and described grappling with potential future losses. Most of the participants were married or cohabitating, and as such the impact of cognitive symptoms was primarily discussed in relation to their romantic relationships; however, some participants also reflected on the impact these symptoms had or could have on their relationship with their children, grandchildren, friends, or even colleagues. Subtheme 3.1: Changes in cognition have affected my relationship from my loved ones’ perspective Participants discussed the impact of cognitive symptoms on their relationships as being from one of two perspectives; the first perspective was that cognitive decline affects their relationship from their loved one’s perspective. Cognitive symptoms increased burden for participants’ loved ones and several participants felt they were no longer able to fill the same role in their loved one’s life as before. P12: “I used to do the [planning]. [Wife] has to do that now. And I used to do all that stuff.” – planning P7: “That’s pretty important, really to me. Because it affects not only me, but [wife]. And we have two grandsons that live with us. And I feel to some degree they rely on me.” – agitation Some participants reflected that they had observed the impact of HD symptoms on their parents’ relationship and described concerns that similar dynamics would occur in their own. P4: Yeah, if that keeps going, intensifying that’s gonna probably put a bit of a- a- a strain on him [my husband] to sort of keep dragging me on to stuff, and I’ve seen it happen with my mum and dad as well…” – fatigue Subtheme 3.2: Changes in cognition have affected my relationships from my perspective In this subtheme, we captured participant perceptions of how cognitive symptoms made them feel more vulnerable in their relationships and their discomfort with increased reliance on others as they lost autonomy. Participants highlighted how cognitive symptoms have contributed to losing relationships and friendships in the past, and how they feel more disconnected from their loved ones who do not understand the changes they are experiencing. P13: “You know, I don’t have a lot of friends because of the disease, drove a lot away.” – emotional lability A key discussion point in multiple interviews was the role of cognitive symptoms in losing personal autonomy. Participants noted that they were either already reliant on family members or anticipated becoming more reliant on others, which was viewed negatively. P8: “So, I don’t want to end up like him [HD family member], where I’m totally dependent on somebody to do everything for me.” P9: “That’s probably very important for me because I just, I don’t like having to rely on people.” Several participants stated that they used strategies to mitigate the impact of their symptoms to their relationships. For example, one participant stated that she was impulsive in conversations and would not ask her children about key events in their lives or would dominate conversations. To address this, she created plans with discussion topics when calling her children on the phone. P15: “I should be able to just have these discussions…with my children without having to plan anything. So, that’s been a bit…of a challenge for me.” – impulsivity Table 3 Themes produced from interviews with HD participants. Theme Subtheme 1. Changes in cognition affect my everyday activities. 1. Changes in cognition affect my ability to work. 2. Changes in cognition affect my leisure activities. 3. Changes in cognition affect my ability to drive. 4. Changes in cognition affect my ability to do domestic activities. 5. Changes in cognition affect my finances. 6. Changes in cognition affect my ability to interact and socialise. 2. Changes in cognition affect my wellbeing. 3. Changes in cognition affect my relationships. 1. Changes in cognition have affected my relationship from my loved one’s perspective. 2. Changes in cognition have affected my relationship from my perspective. Table 4 Representation of participants by theme: HD participants. Themes % Representation Symptom Changes in cognition affect everyday activities. 100% (18/18) Changes in cognition affect my ability to work. 72% (13/18) Memory (10/18) Changes in cognition affect my leisure activities. 78% (14/18) Psychomotor Rhythm (10/18) Changes in cognition affect my driving. 78% (14/18) Switching Attention (5/18) Changes in cognition affect my domestic activities. 89% (16/18) Problem Solving (8/18) Changes in cognition affect my finances. 39% (7/18) Impulsivity (4/18) Changes in cognition affect my ability to interact and socialise. 89% (16/18) Memory, Processing Speed (10/18) Changes in cognition affect my wellbeing. 83% (15/18) Memory (9/18) Changes in cognition affect my relationships. 89% (16/18) Changes in cognition have affected my relationship from my loved one’s perspective. 83% (15/18) Mood, Mental Health, and Personality (6/18) Changes in cognition have affected my relationships from my perspective. 83% (15/18) Avoiding Complex Activities (5/18) Discussion To our knowledge, this study is the first to systematically identify and rate individual cognitive symptoms in HD, as well as to map them to their perceived impacts using a symptom mapping methodology. Our findings align with previous lived experience research showing that cognitive decline is important and bothersome to people with HD [ 11 – 14 ]. This work adds to the growing body of literature on the lived experience of HD and will be useful to guide patient-focused clinical trial design, including the development of clinically meaningful cognitive endpoints [ 2 ]. Participants described worsened wellbeing as an impact of cognitive symptoms, aligning with existing research showing an association between cognitive decline and reduced quality of life in people living with HD [ 23 , 24 ]. Specifically, changes in executive function, inattention, memory, and processing speed have been associated with both diminished quality of life and increased depression in HD [ 23 , 24 , 37 ]. Notably, participants in our study most frequently identified memory changes as affecting their wellbeing and mental health. Memory difficulties were also consistently rated as both important and bothersome, highlighting this domain as a meaningful concept of interest from the patient perspective and priority target for future clinical trials. Domestic activities, work activities, communication, driving, and managing finances were all areas that our participants reported as affected by cognitive changes, consistent with previous research [ 21 , 22 ]. Symptoms like memory, processing speed, switching attention, and impulsivity were viewed as relevant to these areas of life and may be important outcomes in clinical trials. Additionally, changes in psychomotor rhythm were identified as contributing to difficulties engaging in hobby or enjoyment activities. Engagement in leisure activities is protective against cognitive and functional decline [ 36 ]. Our findings suggest that impairments in psychomotor function contribute to reduced leisure activity engagement and therefore could be an important area to target in future clinical trials. Personal relationships are commonly affected by changes due to HD [ 38 , 39 ]; however, our study is the first to explore the impact of specific cognitive and behavioural changes to personal relationships in this population. Interestingly, participants discussed the impact on their relationships in two ways: how they felt the relationship had been affected for their loved ones, and how they felt the relationship had been affected for them. We found that people with HD primarily viewed changes in their mood, mental health, and personality as contributing to difficulties in their relationship for their loved ones as participants felt unable to fulfill emotional obligations or previous roles in their relationships. Family members of people with HD often report feeling a sense of loss for their relationship [ 40 ] and patient mental health is a key predictor of caregiver burden, supporting our findings [ 41 ]. Conversely, cognitive changes such as avoiding complex activities were more frequently discussed as affecting relationships from the perspective of people with HD. Specifically, participants discussed how cognitive decline meant losing personal autonomy and needing to rely on others. Previous research identified loss of autonomy as a key area of concern for people with HD as they become gradually more reliant on both paid and gratuitous caregivers [ 42 ]. Interventions that support both cognitive and behavioural or psychiatric changes are important to support both people with HD and their loved ones. A final key finding from our study was that participants could view symptoms as important but not bothersome. For example, problem solving was the symptom most frequently viewed as important by participants (94.44%) but was only viewed as bothersome by 50% of our sample. The discrepancy between how important symptoms were rated versus how bothersome they actually are to daily life is consistent with previous research conducted in PD where participants identified symptoms as important due to their anticipated future impact, even when not currently bothersome [ 9 ]. This finding was usually unidirectional, meaning symptoms rated as bothersome were typically also rated as important. Our findings suggest that cognitive symptoms do not necessarily need to be presently affecting everyday life for people with HD to view them as important concepts of interest. Assessing cognitive concepts of interest that are not yet bothersome in clinical trials may still be a meaningful outcome from the patient perspective. Additionally, early assessment of important symptoms will be helpful to establish when symptoms become bothersome and ensure that cognitive endpoints used in clinical trials can adequately capture the rate of symptom change over time. Strengths, Limitations, and Areas for Future Research A unique contribution and strength of our study design was the use of symptom mapping methodology. Symptom mapping is a novel methodology that uses card sorting to identify and delineate important symptoms from the patient perspective and has demonstrated feasibility in multiple populations, including PD [ 9 , 34 ] and asthma [ 26 , 32 , 33 ]. In HD research, symptom mapping may be particularly helpful to facilitate interviews. People with HD often experience difficulties with memory recall and sustained attention [ 19 , 20 , 43 ], making traditional interviews cognitively demanding, especially when discussing abstract concepts like cognition. Interview guidelines for HD encourage the use of prompting [ 44 ], and symptom mapping provides a visual aid that helps maintain focus on the conversation topic and reduce the need for verbal redirection. Our study supports the feasibility of symptom mapping in this population and suggests that it may be a useful tool for future studies conducting qualitative research in HD. One limitation in our study was the use of a cross-sectional study design. We captured participant perceptions around their cognitive symptoms at a single time point and did not capture whether or how perceptions evolve with disease progression. Longitudinal research in PD suggests that there can be changes in the perceived importance of symptoms over time [ 45 ]. Similarly, cross-sectional research exploring the frequency of impacts at different AD stages found differences between group perceptions [ 3 ]. Like PD and AD, HD is a slowly progressing disease and it is likely that as patients move through different stages of life and disease, they will have different priorities and may perceive different symptoms and impacts as more important. Understanding meaningful outcomes at different stages of progressive diseases is an important consideration for clinical trial design in the view of the FDA [ 46 ]. For example, the FDA require that outcome measures used in endpoint strategies be tailored to the specified context of use [ 2 ]; that is, the outcomes assessed should be meaningful for the population under investigation and the measure should be capable of capturing changes in meaningful symptoms within the expected timeframe of the trial. Exploring longitudinal perceptions on important and bothersome symptoms and their impacts will be helpful to create fit-for-purpose outcome measures for HD clinical trial aimed at specific HD stages and over different durations. Another consideration in our study is that participants may be underreporting or underestimating symptoms and their impacts due to reduced insight, which is characteristic in HD [ 37 – 49 ]. As such, our findings should be interpreted as a minimum estimate of symptom bothersomeness. Reduced insight into symptoms and their impact on everyday activities often leads to discrepancies between the perspective of people with HD and other people in their lives [ 11 ]. Patients are key stakeholders in clinical research and understanding their direct experiences is crucial for patient-focused drug development [ 46 , 50 ]; nevertheless, including family members in lived experience research is a valuable way to more accurately understand the day-to-day experience of cognitive symptoms in HD. Finally, our study was completed in a small, demographically limited Caucasian sample of Australians with HD. Perceptions of illnesses and the impact illness has differs between different countries and population groups [ 51 – 53 ]; Therefore, our findings may not be representative of the experience of people with HD in other countries or that are part of different racial or ethnic groups. Future research should consider exploring meaningful cognitive symptoms from other diverse perspectives. Conclusions Our study provides patient-experience data on the bothersomeness, importance, and functional impacts of different cognitive symptoms in HD. The findings from our study can be used to support the development of patient-centred intervention development, including guiding selection and development of clinically meaningful outcome measures that capture the patient experience. Declarations Acknowledgements Ms Cali Roiboit is a recipient of the Research Training Program (RTP) scholarship funded by the Australian Government. Professor Julie Stout is the recipient of an Australian National Health and Medical Research Investigator grant. Author Contribution All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Cali Roiboit. The first draft of the manuscript was written by Cali Roiboit and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Data Availability The data supporting the findings of this study are available within the article and supplementary materials. Additional de-identified data may be provided on request. Declaration of Competing Interests Ms Cali M Roiboit is a recipient of the Research Training Program (RTP) scholarship funded by the Australian Government. Professor Julie C Stout is the recipient of an Australian National Health and Medical Research Investigator grant. Professor Stout has consulted and served advisory boards for several sponsors and clinical trials over the past 20 years and is a director of a contract research organisation that facilitates the implementation of cognitive assessments in HD clinical trials. Professor Stout has been funded by the CHDI Foundation for projects aimed at developing a cognitive assessment battery for HD clinical trials. Professor Stout provides consultation services for HD clinical trials via Stout Neuropsych Pty Ltd, and is a director of Zindametrix Pty Ltd, which facilitates the implementation of the HD-CAB in clinical trials. Associate Professor Jennifer R Mammen has consulted for and/or received research support from The Michael J Fox Foundation for Parkinson’s Research, Critical Path for Parkinson’s, National Institutes of Health/NINR, Sigma Theta Tau International, and Lundbeck. Associate Professor Jamie L Adams has received research support from the Michael J. Fox Foundation for Parkinson’s Research, Critical Path for Parkinson’s, NIH/NINDS, Biogen, the Huntington Study Group, and PhotoPharmics; received compensation as a consultant/steering committee/advisory board member from the Huntington Study Group, the Parkinson Study Group, AbbVie, VisualDx, BioSensics, Sana Biotechnology, Neuron23, Lundbeck, Biohaven, and the Michael J. Fox Foundation for Parkinson’s Research; received honoraria for speaking from the Huntington Study Group, the Parkinson Study Group, and American Neurological Association. Both Associate Professors Jennifer Mammen and Jamie Adams have received research funding from the U.S. Food and Drug Administration. Ethical Consideration Ethical approval for this study was provided by the Monash University Human Research Ethics Committee (MUHREC ID: 36930). Consent to Participate All participants provided written informed consent prior to participating in any study activities. Consent for Publication All participants provided written informed consent for their de-identified data to be used for research purposes. References Food, F. D. A. U. S. & Administration, D. FDA; [cited 2023 Jan 25]. Patient-Focused Drug Development: Collecting Comprehensive and Representative Input. (2021). Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/patient-focused-drug-development-collecting-comprehensive-and-representative-input FDA. U.S. Food and Drug Administration. Patient-Focused Drug Development: Selecting, Developing, or Modifying Fit-for-Purpose Clinical Outcome Assessments. (2022). Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/patient-focused-drug-development-selecting-developing-or-modifying-fit-purpose-clinical-outcome DiBenedetti, D. B. et al. 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Huntington disease: Clinical care and evaluation. Neurology 29 , 1–1 (1979). Hughes, S. et al. Development and Psychometric Properties of a New Brief, Yet Comprehensive, Behavioral Questionnaire for Huntington’s Disease. Mov. Disord Clin. Pract. 10 , 427–233 (2023). Mammen, J. R., Rhee, H., Norton, S. A. & Butz, A. M. Perceptions and experiences underlying self-management and reporting of symptoms in teens with asthma. J. Asthma . 54 , 143–152 (2017). Mammen, J. R. et al. A mixed-methods analysis of younger adults’ perceptions of asthma, self-management, and preventive care: This isn’t helping me none. Clin. Exp. Allergy . 51 , 63–77 (2021). Mammen, J. R. et al. Mapping Relevance of Digital Measures to Meaningful Symptoms and Impacts in Early Parkinson’s Disease. J. Parkinsons Dis. 13 , 589–607 (2023). Braun, V. & Clarke, V. Thematic Analysis: A Practical Guide (SAGE Publications Ltd, 2022). Bilal, H. et al. The Lived Experiences of Depression in Huntington’s Disease: A Qualitative Study. J. Huntingtons Dis. 11 , 321–335 (2022). Migliore, S. et al. Cognitive Reserve in Early Manifest Huntington Disease Patients: Leisure Time Is Associated with Lower Cognitive and Functional Impairment. J. Pers. Med. 12 , 1–12 (2022). Kaptein, A. A. et al. Quality of life in couples living with Huntington’s disease: the role of patients’ and partners’ illness perceptions. Qual. Life Res. 16 , 793–801 (2007). Reininghaus, E. et al. Body Image, and Partnership in Chronic Illness. J. Nerv. Ment Dis. 200 , 716–720 (2012). Williams, J. K. et al. The emotional experiences of family carers in Huntington disease. J. Adv. Nurs. 65 , 789–798 (2009). Banaszkiewicz, K. et al. Huntington’s disease from the patient, caregiver and physician’s perspectives: three sides of the same coin? J. Neural Transm (Vienna) . 119 , 1361–1365 (2012). Varela, L. E., Arias, M. M., Martorell-Poveda, M. A., Giraldo, C. V. & Estrada-Acuña, R. A. Beyond the clinical context: the process of losing oneself living with Huntington’s disease. Orphanet J. Rare Dis. 17 , 184 (2022). Montoya, A. et al. Episodic memory impairment in Huntington’s disease: A meta-analysis. Neuropsychologia 44 , 1984–1994 (2006). LaDonna, K. A. & Ravenek, M. J. Challenges & Strategies for Conducting Qualitative Research with Persons Diagnosed with Rare Movement Disorders. Qualitative Rep. 19 , 1–18 (2014). Mammen, J. R. et al. Longitudinal qualitative assessment of meaningful symptoms and relevance of WATCH-PD digital measures for people with early Parkinson’s. J. Neurol. 272 , 114 (2025). Rare Diseases, F. D. A. Rare Diseases: Considerations for the Development of Drugs and Biological Products. (2023). Available from: https://www.fda.gov/media/119757/download Ho, A. K., Robbins, A. O. G. & Barker, R. A. Huntington’s disease patients have selective problems with insight. Mov. Disord . 21 , 385–389 (2006). McCusker, E. & Loy, C. T. The Many Facets of Unawareness in Huntington Disease. Tremor Other Hyperkinet Mov. (N Y) . 4 , 257 (2014). Sitek, E. J., Thompson, J. C., Craufurd, D. & Snowden, J. S. Unawareness of deficits in Huntington’s disease. J. Huntingtons Dis. 3 , 125–135 (2014). Food, F. D. A. U. S. & Administration, D. FDA; [cited 2023 Jan 25]. Patient-Focused Drug Development: Methods to Identify What Is Important to Patients. (2022). Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/patient-focused-drug-development-methods-identify-what-important-patients Erbil, P., Razavi, D., Farvacques, C., Bilge, N. & Van Houtte, P. P. Cancer patients psychological adjustment and perception of illness: Cultural differences between Belgium and Turkey. Support Care Cancer . 4 , 455–461 (1996). Kuppens, K. et al. Do Illness Perceptions in Patients with Fibromyalgia Differ Across Countries? A Comparative Study. MYOPAIN 23 , 13–20 (2015). Ruiz-Montero, P. J., Van Wilgen, C. P., Segura-Jiménez, V., Carbonell-Baeza, A. & Delgado-Fernández, M. Illness perception and fibromyalgia impact on female patients from Spain and the Netherlands: do cultural differences exist? Rheumatol. Int. 35 , 1985–1993 (2015). Additional Declarations Competing interest reported. Ms Cali M Roiboit is a recipient of the Research Training Program (RTP) scholarship funded by the Australian Government. Professor Julie C Stout is the recipient of an Australian National Health and Medical Research Investigator grant. Professor Stout has consulted and served advisory boards for several sponsors and clinical trials over the past 20 years and is a director of a contract research organisation that facilitates the implementation of cognitive assessments in HD clinical trials. Professor Stout has been funded by the CHDI Foundation for projects aimed at developing a cognitive assessment battery for HD clinical trials. Professor Stout provides consultation services for HD clinical trials via Stout Neuropsych Pty Ltd, and is a director of Zindametrix Pty Ltd, which facilitates the implementation of the HD-CAB in clinical trials. Associate Professor Jennifer R Mammen has consulted for and/or received research support from The Michael J Fox Foundation for Parkinson’s Research, Critical Path for Parkinson’s, National Institutes of Health/NINR, Sigma Theta Tau International, and Lundbeck. Associate Professor Jamie L Adams has received research support from the Michael J. Fox Foundation for Parkinson’s Research, Critical Path for Parkinson’s, NIH/NINDS, Biogen, the Huntington Study Group, and PhotoPharmics; received compensation as a consultant/steering committee/advisory board member from the Huntington Study Group, the Parkinson Study Group, AbbVie, VisualDx, BioSensics, Sana Biotechnology, Neuron23, Lundbeck, Biohaven, and the Michael J. Fox Foundation for Parkinson’s Research; received honoraria for speaking from the Huntington Study Group, the Parkinson Study Group, and American Neurological Association. Both Associate Professors Jennifer Mammen and Jamie Adams have received research funding from the U.S. Food and Drug Administration. Supplementary Files SupplementaryMaterials.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6988143","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":486621666,"identity":"bcfe819e-b6af-431b-ae14-b521bc93f438","order_by":0,"name":"Cali M Roiboit","email":"","orcid":"","institution":"Monash University","correspondingAuthor":false,"prefix":"","firstName":"Cali","middleName":"M","lastName":"Roiboit","suffix":""},{"id":486621667,"identity":"06bc9ad3-1044-4feb-a391-04a07602f566","order_by":1,"name":"Jennifer R Mammen","email":"","orcid":"","institution":"University of Massachusetts","correspondingAuthor":false,"prefix":"","firstName":"Jennifer","middleName":"R","lastName":"Mammen","suffix":""},{"id":486621668,"identity":"8eda8148-269b-4d84-8cf4-eef3bebd65f3","order_by":2,"name":"Jamie L Adams","email":"","orcid":"","institution":"University of Rochester","correspondingAuthor":false,"prefix":"","firstName":"Jamie","middleName":"L","lastName":"Adams","suffix":""},{"id":486621669,"identity":"3dd2ad58-f1f2-45a6-9942-b753fcdff03a","order_by":3,"name":"Julie C Stout","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA70lEQVRIiWNgGAWjYBACxgbmhgMw9gMwJQHEPHi1MIK1ANUxMxsQpQWkCaqOmU2CKC3MMxIbD3xgqKvjl8g/VnWj4o68/OwGxgdv2/DYMSOx4eAMhsMSkjOS2W7nnHlmuOHOAWbDuQS0HOZhOCBhcAOoJbftMOMGiQQ2aV5CWv4w1IG1FAO12M+fkcD+m6AWoJfAWpiBWhIbbiSwMePV0vOw4WCPwWHJmT2PjaVzzhxO3nAjsVlyzjncWgzbkw9/+FFRx8/Pnvjwc07FYdv5M5IPfnhThkdLA4g0QLW5Abd6IJDHKzsKRsEoGAWjAAQAbjFVZnuyRhIAAAAASUVORK5CYII=","orcid":"","institution":"Monash University","correspondingAuthor":true,"prefix":"","firstName":"Julie","middleName":"C","lastName":"Stout","suffix":""}],"badges":[],"createdAt":"2025-06-27 05:38:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6988143/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6988143/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87242242,"identity":"6a6f6d5f-bc53-4c9d-a644-15afc123b8bd","added_by":"auto","created_at":"2025-07-22 01:43:53","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":507902,"visible":true,"origin":"","legend":"\u003cp\u003eFrequency of importance ratings for each symptom ordered from left to right based on the number of participants who rated an item as Most or Very Important (Dark blue portion of each bar).\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6988143/v1/9141b97dcd9031506b28cbe7.jpg"},{"id":87242244,"identity":"b5118ef2-9e85-43f6-ac58-c1992f13e907","added_by":"auto","created_at":"2025-07-22 01:43:53","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":535298,"visible":true,"origin":"","legend":"\u003cp\u003eFrequency of bothersome ratings for each symptom ordered from left to right based on the number of participants who rated an item as Most or Very Important (Dark blue portion of each bar).\u003c/p\u003e","description":"","filename":"Picture2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6988143/v1/799a3b531452431ec37db3a4.jpg"},{"id":88863625,"identity":"c49ddb77-f3cc-4a9d-8ca1-1c4d206b3f12","added_by":"auto","created_at":"2025-08-12 08:02:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2270412,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6988143/v1/b685c9e5-b4ce-402a-8fa2-4625ac3227fe.pdf"},{"id":87242778,"identity":"9e34397d-5d6c-4e40-bcc4-06025c3dd4a2","added_by":"auto","created_at":"2025-07-22 01:51:53","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":487959,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterials.docx","url":"https://assets-eu.researchsquare.com/files/rs-6988143/v1/79e0970add655db89f80176c.docx"}],"financialInterests":"Competing interest reported. Ms Cali M Roiboit is a recipient of the Research Training Program (RTP) scholarship funded by the Australian Government. Professor Julie C Stout is the recipient of an Australian National Health and Medical Research Investigator grant. Professor Stout has consulted and served advisory boards for several sponsors and clinical trials over the past 20 years and is a director of a contract research organisation that facilitates the implementation of cognitive assessments in HD clinical trials. Professor Stout has been funded by the CHDI Foundation for projects aimed at developing a cognitive assessment battery for HD clinical trials. Professor Stout provides consultation services for HD clinical trials via Stout Neuropsych Pty Ltd, and is a director of Zindametrix Pty Ltd, which facilitates the implementation of the HD-CAB in clinical trials. Associate Professor Jennifer R Mammen has consulted for and/or received research support from The Michael J Fox Foundation for Parkinson’s Research, Critical Path for Parkinson’s, National Institutes of Health/NINR, Sigma Theta Tau International, and Lundbeck. Associate Professor Jamie L Adams has received research support from the Michael J. Fox Foundation for Parkinson’s Research, Critical Path for Parkinson’s, NIH/NINDS, Biogen, the Huntington Study Group, and PhotoPharmics; received compensation as a consultant/steering committee/advisory board member from the Huntington Study Group, the Parkinson Study Group, AbbVie, VisualDx, BioSensics, Sana Biotechnology, Neuron23, Lundbeck, Biohaven, and the Michael J. Fox Foundation for Parkinson’s Research; received honoraria for speaking from the Huntington Study Group, the Parkinson Study Group, and American Neurological Association. Both Associate Professors Jennifer Mammen and Jamie Adams have received research funding from the U.S. Food and Drug Administration.","formattedTitle":"Identifying and Mapping Meaningful Cognitive Symptoms and their Impacts in Huntington’s Disease","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe Patient Focused Drug Development (PFDD) guidance series released by the U.S. Food and Drug Administration (FDA) emphasises the importance of integrating patient experience data at all stages of clinical trial design [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Patient experience data provides information about a patients\u0026rsquo; experiences with a disease or condition, including its symptoms, the impact to function and quality of life, and patient preferences for priorities in clinical trials [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] The selection and development of efficacy endpoints is an aspect of clinical trial design where patient experience data is viewed as especially important. Clinical trial endpoints must reflect relevant \u0026lsquo;Concepts of Interest\u0026rsquo;, which are signs, symptoms or clinical events that are considered clinically meaningful to patients [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eUsing the guidance offered in the FDA\u0026rsquo;s PFDD series, we and others are working to identify disease symptoms and impacts that are meaningful to patients and designing clinical trials efficacy endpoints to align with patient priorities and values. For example, the meaningfulness of particular disease symptoms has been studied in Alzheimer\u0026rsquo;s disease (AD) [\u003cspan additionalcitationids=\"CR4 CR5 CR6\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] and Parkinson\u0026rsquo;s disease (PD) [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] using a mix of qualitative and quantitative methodologies (e.g., interviews, surveys). These studies are instrumental in shaping patient-focused clinical research by identifying patient priorities for clinical trials and clinically meaningful concepts of interest to inform endpoint strategies.\u003c/p\u003e\u003cp\u003ePatient-experience data is also of increasing interest for informing clinical trial design in Huntington\u0026rsquo;s disease (HD), which is an autosomal dominant neurodegenerative disorder characterised by motor dysfunction, cognitive decline, and neuropsychiatric symptoms [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. To date, HD patient experience data have been described in a white paper from the FDA as part of their \u0026lsquo;Voice of the Patient\u0026rsquo; series, as well as in several additional published studies [\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. All studies described non-motor symptoms, such as cognitive and executive dysfunction, as the most bothersome disease features with greatest impact from the perspective of people with HD and caregivers, in turn identifying cognition as a high priority target for the development of new treatments.\u003c/p\u003e\u003cp\u003eCognitive decline in HD emerges early in the disease course [\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] and is characterised by gradual declines in processing and psychomotor speed, memory retrieval, attention, and executive function [\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Cognitive deficits contribute to difficulties in everyday activities, including domestic tasks, work activities, driving, communication, and relationships [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], and are associated with declining quality of life [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Despite people with HD and their caregivers assigning high significance to cognitive decline in their experience of HD, systematic research has not yet explored the patient perspective regarding the relevance of particular cognitive symptoms, nor the impact of cognitive decline on daily functioning. Identifying cognitive concepts of interest that are \u0026lsquo;clinically meaningful\u0026rsquo; is an essential step for informing targeted treatment development, and for designing meaningful cognitive endpoint measures for clinical trials [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. The FDA defines \u0026lsquo;clinically meaningful\u0026rsquo; concepts of interest as symptoms that have a recognisable impact to everyday function, quality of life, or survival [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn this study we aimed to build on previous work collecting patient-experience data in HD and identify cognitive symptoms that, from the patient perspective, are important and bothersome, and to map these symptoms to their everyday impacts. We used a symptom mapping approach, including rating scales, semi-structured interviews, and qualitative analysis, adapted from the work of Mammen et al. in PD [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e"},{"header":"Methodology","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eStudy Design\u003c/h2\u003e\n \u003cp\u003eWe used a cross-sectional qualitative design using semi-structured interviews and symptom mapping. The findings from this study are part of a larger study design that included completing the Huntington\u0026rsquo;s Disease Cognitive Assessment Battery (HD-CAB) [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e] and a second interview exploring perceptions around cognitive testing. This study was approved by the Monash University Human Research Ethics Committee (MUHREC ID: 36930) and all research was performed in accordance with relevant guidelines and regulations. Study procedures were in accordance with the Declaration of Helsinki.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eParticipants\u003c/h3\u003e\n\u003cp\u003eWe recruited 18 CAG expansion carriers (CAG\u0026thinsp;\u0026ge;\u0026thinsp;38) experiencing either subjective or overt signs and symptoms of HD (see Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e for participant characteristics). Participants were recruited from various sources, including HD research volunteer databases, social media, and local specialist clinics.\u003c/p\u003e\n\u003cp\u003eWe intentionally kept inclusion and exclusion criteria broad to include a clinically varied sample. Participants were eligible for the study if they had undergone genetic or predictive testing, were experiencing subjective or overt signs and symptoms of HD and scored between 7 and 13 on the Unified Huntington\u0026rsquo;s Disease Rating Scale (UHDRS) Total Functional Capacity (TFC) scale [\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e]. Exclusion criteria included neurological disorders except for HD and neurodevelopmental disorders, history of acquired brain injury, current excessive alcohol or drug use, and self-reported mental health disorders that may reasonably make it difficult to participate in the interview. We staged participants\u0026rsquo; disease progression for demographic purposes using the Shoulson-Fahn Staging System and the Huntington\u0026rsquo;s Disease Integrated Staging System (HD-ISS) [\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e]. The Shoulson-Fahn Staging system uses ratings on the TFC to stage functional impairment in HD across five stages ranging from Stage 1 (TFC\u0026thinsp;=\u0026thinsp;11\u0026ndash;13), Stage 2 (TFC\u0026thinsp;=\u0026thinsp;7\u0026ndash;10), Stage 3 (TFC\u0026thinsp;=\u0026thinsp;3\u0026ndash;6), Stage 4 (TFC\u0026thinsp;=\u0026thinsp;1\u0026ndash;2) and Stage 5 (TFC\u0026thinsp;=\u0026thinsp;0) [\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e]. The HD-ISS uses biological and clinical disease indicators to stage people with HD across four stages, from Stage 0 (CAG\u0026thinsp;\u0026ge;\u0026thinsp;40, no pathological or clinical changes), Stage 1 (detectable pathological changes), Stage 2 (detectable cognitive or motor changes), and Stage 3 (detectable function changes) [\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e]. Twenty people with HD originally agreed to participate in the study. Two participants withdrew prior to the study session due to difficulty finding time to complete the study session or ceasing communication with the research team prior to their scheduled session.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eParticipant characteristics.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMean age in years (SD)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e54.94 (13.39)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRange\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32\u0026ndash;72\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e% Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMean TFC score (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.56 (2.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRange\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u0026ndash;13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMean CAG expansion length (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e42.23 (3.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRange\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38\u0026ndash;52\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMean years of education (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14.62 (1.82)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRange\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11\u0026ndash;17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTFC Stages\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003en\u003c/em\u003e Stage 1 (11\u0026ndash;13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003en\u003c/em\u003e Stage 2 (7\u0026ndash;10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHD-ISS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003en\u003c/em\u003e Stage 0\u0026ndash;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003en\u003c/em\u003e Stage 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003en\u003c/em\u003e Stage 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\"\u003e\u003cem\u003eNote\u003c/em\u003e: TFC\u0026thinsp;=\u0026thinsp;Total Functional Capacity; CAG\u0026thinsp;=\u0026thinsp;cytosine-adenine-guanine; HD-ISS\u0026thinsp;=\u0026thinsp;Huntington\u0026rsquo;s Disease Integrated Staging System. HD-ISS Stage 2 is based on cut-offs derived from the Symbol Digit Modalities Task (SDMT) and/or the UHDRS Total Motor Scale (TMS); we only had access to participant performance on the SDMT. Some participants staged as HD-ISS 0\u0026ndash;1 had received a motor diagnosis.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003ch3\u003eMeasures\u003c/h3\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n \u003ch2\u003eDemographic questionnaire\u003c/h2\u003e\n \u003cp\u003eWe administered a brief demographic questionnaire over the phone when screening participants. We obtained information related to age, gender, education, occupational history, medical history, psychiatric history, and drug and alcohol history, and questions related to HD history (e.g., CAG expansion length, year of diagnosis if known).\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eTotal Functional Capacity (TFC) scale\u003c/h3\u003e\n\u003cp\u003eWe administered the TFC to estimate disease severity. The TFC scale is a clinician-rated subscale of the UHDRS and assesses functional capacity to independently carry out activities such as work, manage finances, personal grooming, hygiene, and the extent to which they need caregiving [\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e]. Participant scores can range from 0\u0026ndash;13, with higher scores indicating better functional capacity and in turn, lesser disease severity.\u003c/p\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eUniversity of California San Diego Huntington\u0026rsquo;s Disease Behaviour Questionnaire (UCSD HDBQ)\u003c/h2\u003e\n \u003cp\u003eCognitive symptoms can be abstract and difficult for people to observe and self-identify; therefore, we used the UCSD HDBQ as a symptom checklist to help participants generate and describe symptoms that they were experiencing. The UCSD HDBQ is a self-report questionnaire which captures 30 cognitive and behavioural symptoms in HD [\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e]. Participants are asked to rate, using a four-point Likert scale ranging from \u003cem\u003eCompletely Disagree\u003c/em\u003e to \u003cem\u003eCompletely Agree\u003c/em\u003e, the extent to which they agree that they have experienced a change in each of the 30 symptoms over past 12 months.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eProcedure\u003c/h3\u003e\n\u003cp\u003eWe adapted procedures from a previous study conducted in PD [\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e]. Interested participants were screened over the phone and invited to attend an in-person study session either at the Monash University Turner Clinics or at their own home. All participants provided written informed consent prior to participating in study activities.\u003c/p\u003e\n\u003cp\u003eParticipants completed the UCSD HDBQ prior to the semi-structured interview. CR (a PhD candidate in clinical neuropsychology) conducted all interview sessions. Interviews aimed to explore participants\u0026rsquo; experience with cognitive symptoms of HD and how these changes have been important for their everyday lives. Interviews ranged from 37 minutes to 127 minutes in length, which included a second cognitive interview, and all interviews were recorded and transcribed verbatim. The semi-structured interviews followed an interview guide (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e), and we used additional prompts as needed (e.g., \u003cem\u003e\u0026ldquo;can you tell me more about that?\u0026rdquo; \u0026ldquo;Can you tell me more about why you gave this rating?\u0026rdquo;\u003c/em\u003e). We refined the interview guide and methodology early in data collection to address any issues that arose.\u003c/p\u003e\n\u003cp\u003eWe started interviews by discussing symptoms that participants reported had worsened over the past 12 months on the UCSD HDBQ. Next, we prompted participants for domains of cognitive function that are commonly impacted in HD, including memory, psychomotor rhythm, planning, problem solving, recognising emotions, processing speed, and switching attention. We asked participants about any other symptoms they felt were important to discuss, including symptoms they were not yet experiencing but believed would be important in the future.\u003c/p\u003e\n\u003cp\u003eWe completed symptom mapping using XMind (version 24.04.10291) to create a detailed map of the participant\u0026rsquo;s experience with their HD symptoms. Symptom mapping is a technique used to delineate meaningful symptoms and their impacts from the patient perspective [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e]. We completed symptom mapping collaboratively with the participant observing and validating data entry throughout the interview (see an example of a completed symptom map in the Supplementary Materials, Appendix \u003cspan class=\"InternalRef\"\u003eA\u003c/span\u003e, Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eA). Symptoms were organised in symptom maps from \u003cem\u003eNot Important, Somewhat Important\u003c/em\u003e and \u003cem\u003eVery or Most Important\u003c/em\u003e, and nodes were attached to each symptom detailing how bothersome participants believed the symptom was to everyday life, ranging from 0. \u003cem\u003eNo Issues Present;\u003c/em\u003e 1. \u003cem\u003eNot Very Bothersome;\u003c/em\u003e 2. \u003cem\u003eSomewhat Bothersome\u003c/em\u003e; 3. \u003cem\u003eVery or Most Bothersome\u003c/em\u003e. Each participant was provided with a \u003cspan\u003e$\u003c/span\u003e40 gift card after completing study activities.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eInterview schedule for symptom mapping interview.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTopic\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eQuestions\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1. Impact of current cognitive symptoms to everyday life.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1. You\u0026rsquo;ve indicated that you have experienced a change in [cognitive symptom]. Can you tell me what that looks like for you?\u003c/p\u003e\n \u003cp\u003e2. How important would you rate this change from not at all, somewhat, to very important to you?\u003c/p\u003e\n \u003cp\u003e3. How bothersome or impactful has this change been to everyday life, from 0 (not present); 1 (not very bothersome); 2 (somewhat bothersome); or 3 (very or most bothersome)?\u003c/p\u003e\n \u003cp\u003e4. How does change in [cognitive symptom] impact your everyday life?\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2. Eliciting any spontaneously reported symptoms.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1. Are there any other changes in how you think or in mental abilities which we have not spoken about that you think might be due to HD? [if YES, return to topic 1].\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3. Eliciting symptoms not currently experienced.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1. There might be some changes in thinking or in mental abilities which you have not noticed but can sometimes happen in HD. When you think about these kinds of changes, are there any that you are more concerned about? [if YES, return to topic 1].\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4. Final questions.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1. Is there anything else about your experience with cognitive symptoms in HD that you\u0026rsquo;d like to share?\u003c/p\u003e\n \u003cp\u003e2. How did you find the symptom mapping process?\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003ch3\u003eAnalysis\u003c/h3\u003e\n\u003cp\u003eCR analysed interview transcripts using Reflexive Thematic Analysis (RTA) [\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e]. Data analysis was based on a primarily deductive approach and was situated within a critical realist paradigm. Transcripts were reviewed for accuracy to ensure they were transcribed verbatim, and annotations were made highlighting interesting observations. CR conducted initial coding of all interview transcripts, then grouped related codes to identify preliminary themes. Codes and themes were reviewed and refined iteratively throughout the course of data analysis, with themes finalised after all transcripts had been analysed. We used a mix of Nvivo (version 14.23.4), and Excel and Word (versions 16.94) to complete our data analysis. CR kept a reflexivity journal throughout data analysis and engaged in discussion with other members of the research team as needed to enhance understanding of codes or themes, and to enhance rigour [\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eWe analysed the symptom maps with content coding using Excel (version 16.94) to code symptom type, frequency, importance, and bothersomeness of symptoms and their impacts. We also used interview transcripts to code any additional data that was not originally included into the symptom map. We classified symptoms as important if they were rated as either \u003cem\u003eSomewhat Important\u003c/em\u003e or \u003cem\u003eVery or Most Important\u003c/em\u003e and classified symptoms as bothersome to everyday life if they were rated as bothersome to any degree, including \u003cem\u003eNot Very Bothersome\u003c/em\u003e, \u003cem\u003eSomewhat Bothersome\u003c/em\u003e, or \u003cem\u003eVery or Most Bothersome\u003c/em\u003e. Coding was completed by CR with input from members of the research team as needed.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe frequency that symptoms were rated as important ranged from 0 to 94.44% and the frequency that symptoms were rated as bothersome ranged from 0 to 83.33%. Symptoms were often rated as important by participants, even if not currently bothersome.\u003c/p\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003eMost Important HD Cognitive Symptoms\u003c/h2\u003e\n \u003cp\u003eParticipants most frequently rated \u003cem\u003eproblem solving\u003c/em\u003e as important (94.44%), with 61.11% of participants rating it as \u003cem\u003eMost or Very Important\u003c/em\u003e and 33.33% rating it as \u003cem\u003eSomewhat Important.\u003c/em\u003e After problem solving, \u003cem\u003ememory\u003c/em\u003e was next most frequently rated as important (88.89%), followed by \u003cem\u003eprocessing speed\u003c/em\u003e (83.33%). These ratings were independent of how bothersome symptoms were rated. Figure \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e shows the frequency of importance ratings for each symptom.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003eMost Bothersome HD Cognitive Symptoms\u003c/h2\u003e\n \u003cp\u003eParticipants most frequently rated \u003cem\u003ememory\u003c/em\u003e as an actively bothersome symptom (83.33%) with 50% reporting it as \u003cem\u003eMost or Very Bothersome\u003c/em\u003e. \u003cem\u003eProcessing speed, time to respond\u003c/em\u003e, and \u003cem\u003eshifting attention\u003c/em\u003e were each rated as bothersome by 72.22% of participants. Of note, processing speed and taking more time to respond were often conceptualised by participants as similar constructs. \u003cem\u003eConcentration\u003c/em\u003e was bothersome to 66.67% of the sample. These ratings were independent of how important symptoms were rated. Figure \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e shows the frequency of bothersome ratings for each symptom.\u003c/p\u003e\n \u003cp\u003eWe identified three themes and eight subthemes from interviews (see Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Themes and subthemes were focused on participant perceptions of how different cognitive changes affected their everyday life and why they thought these changes were important. Tables \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e shows the percentage of the sample that were represented by each theme and subtheme, as well as the symptom that was most frequently mapped to each theme. Additional quotes are presented in the Supplementary Materials (Appendix \u003cspan class=\"InternalRef\"\u003eB\u003c/span\u003e, Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eB).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n \u003ch2\u003eTheme 1: Changes in cognition affect my everyday activities\u003c/h2\u003e\n \u003cp\u003eThe participants in our study were at different stages of disease progression and were therefore experiencing different levels of functional impairment. Given the progressive nature of HD, some participants detailed specific ways that cognitive changes had already affected their functional abilities whereas others discussed how they anticipated future symptoms would affect their lives. This theme also captured participants\u0026apos; current reliance on cognitive skills for daily activities, suggesting that deterioration in these skills would threaten their ability to engage in normal tasks.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eSubtheme 1.1: Changes in cognition affect my ability to work\u003c/strong\u003e.\u003c/p\u003e\n \u003cp\u003eParticipants discussed how their cognitive symptoms contributed to difficulties with work. The participants in our sample had varied employment situations: some participants were still working full time, whereas others had transitioned to part-time or supported work, or had ceased work due to HD symptoms. Several participants reported that they were retired from paid employment and instead were focused on volunteering.\u003c/p\u003e\n \u003cp\u003eP14: \u0026ldquo;Because it [memory changes] meant that I couldn\u0026rsquo;t do a particular quality of work. So, I\u0026rsquo;m now on income protection.\u0026rdquo; - \u003cem\u003ememory\u003c/em\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n \u003ch2\u003e\u003cstrong\u003eSubtheme 1.2: Changes in cognition affect my leisure activities\u003c/strong\u003e\u003c/h2\u003e\n \u003cp\u003eMany participants discussed how cognitive decline had affected their leisure activities, such as playing or watching sport, playing instruments, dancing, collecting, or otherwise spending time with their friends and family.\u003c/p\u003e\n \u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003eP12: \u0026ldquo;\u0026hellip; it\u0026rsquo;s annoying. I play guitar and now can\u0026rsquo;t keep the beat\u0026hellip;Yeah, in a band\u0026hellip;with the kids and that.\u0026rdquo; - \u003cem\u003epsychomotor rhythm\u003c/em\u003e\u003c/p\u003e\n \u003c/div\u003e\n \u003cp\u003eSome participants also highlighted that while they were still capable of doing their hobbies, difficulties with increased fatigue and amotivation precluded them from completing those activities.\u003c/p\u003e\n \u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003eP6: \u0026ldquo;So, there\u0026rsquo;s a whole list of the things I used to do, activities that I don\u0026rsquo;t do anymore. I don\u0026rsquo;t play golf, \u0026hellip; I used to work on a family tree\u0026hellip;collected coins, I pretty much haven\u0026rsquo;t done any of those things.\u0026rdquo; \u0026ndash; \u003cem\u003eamotivation/loss of interest\u003c/em\u003e\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\n \u003ch2\u003eSubtheme 1.3: Changes in cognition affect my ability to drive\u003c/h2\u003e\n \u003cp\u003eLike other areas of function, our sample included participants who experienced different levels of driving impairment. Some participants reported that they were no longer driving or had restrictions on their licence due to their HD, while others continued to drive unrestricted.\u003c/p\u003e\n \u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003eP5: \u0026ldquo;I\u0026rsquo;ll be driving the car and the missus will want a conversation as you\u0026rsquo;re driving through the barrel of traffic\u0026hellip; \u0026ldquo;yeah hang on, I need to concentrate on the road here\u0026rdquo;.\u0026rdquo; \u0026ndash; \u003cem\u003eswitching attention\u003c/em\u003e\u003c/p\u003e\n \u003c/div\u003e\n \u003cp\u003eTwo participants lived outside of the metropolitan area and highlighted that being able to drive was important to them for their independence.\u003c/p\u003e\n \u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003eP18: \u0026ldquo;This place ain\u0026rsquo;t the easiest place to get a bus and I hate public transport. So, driving a car is beautiful.\u0026rdquo;\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\n \u003ch2\u003eSubtheme 1.4: Changes in cognition affect my ability to do domestic activities\u003c/h2\u003e\n \u003cp\u003eParticipants discussed the impact of cognitive changes for their ability to complete domestic activities, such as cleaning, cooking, or doing the gardening. Some participants described needing to use adaptations to complete tasks, whereas others noted that they no longer can complete regular activities. Several participants reported that they received funding through government schemes to help manage some of their domestic chores.\u003c/p\u003e\n \u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003eP15: \u0026ldquo;I can\u0026rsquo;t multitask, that\u0026rsquo;s impossible\u0026hellip;when I\u0026rsquo;m cooking. I have to do one thing at a time\u0026hellip;so, it means preparing the meals, that\u0026rsquo;s just preparing meals. If I do the washing, I just do the washing. If I do the cleaning, I just do the cleaning.\u0026rdquo; \u0026ndash; \u003cem\u003eswitching attention\u003c/em\u003e\u003c/p\u003e\n \u003c/div\u003e\n \u003cp\u003eOne participant stated that he had the resources to outsource certain tasks, which mitigated the impact of cognitive changes on his day-to-day life.\u003c/p\u003e\n \u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003eP17: \u0026ldquo;\u0026hellip;I don\u0026rsquo;t have to do [the gardens] anymore. I can afford to have someone do it. And I don\u0026rsquo;t really like doing it.\u0026rdquo; \u0026ndash; \u003cem\u003eavoiding complex activities\u003c/em\u003e\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\n \u003ch2\u003eSubtheme 1.5: Changes in cognition affect my finances\u003c/h2\u003e\n \u003cp\u003eCognitive symptoms were also viewed as important for financial management, including paying bills on time, impulsively shopping, or acquiring debt. Several participants stated they were no longer primarily in charge of the finances, with their spouse or other family members taking over financial management tasks. One participant reported that they had recently lost control of their finances and were required to appoint an alternate financial decision maker.\u003c/p\u003e\n \u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003eP4: \u0026ldquo;Not all the time, just on the odd occasion it gets a bit, yeah\u0026hellip;I sorta have regret\u0026hellip;on what I\u0026rsquo;ve done\u0026hellip;. Luckily not in crazy amounts of debt.\u0026rdquo; \u0026ndash; \u003cem\u003eimpulsivity\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003eP18: \u0026ldquo;So, she thinks I\u0026rsquo;m not able to manage my finances\u0026hellip;\u0026rdquo; \u0026ndash; \u003cem\u003eavoiding complex activities\u003c/em\u003e\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\n \u003ch2\u003eSubtheme 1.6: Changes in cognition affect my ability to interact and socialise\u003c/h2\u003e\n \u003cp\u003eAlmost all participants stated that cognitive symptoms had affected their ability to interact and socialise with others. Participants described how they have more difficulty engaging in conversation due to taking longer to process and respond to information and highlighted that they would sometimes act inappropriately in social settings. These difficulties often made socialising more anxiety inducing, and some participants noted that they avoided interacting as a result.\u003c/p\u003e\n \u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003eP16: \u0026ldquo;But [laugh] [I] don\u0026rsquo;t spit it out, don\u0026rsquo;t think of the answer\u0026hellip;, I\u0026rsquo;ve created a, like, four-second gap. He\u0026rsquo;s looking at me, and I\u0026rsquo;m looking at him \u0026hellip;I\u0026rsquo;m like, double checking. By the time I\u0026rsquo;ve gone from all that in me head, \u0026hellip;it\u0026rsquo;s like four seconds, five seconds, just to say yes or no.\u0026rdquo; \u0026ndash; \u003cem\u003eprocessing speed\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003eP17: \u0026ldquo;\u0026hellip;hard right turns in a conversation can sometimes really throw me and I find myself just dipping out.\u0026rdquo; \u0026ndash; \u003cem\u003eswitching attention\u003c/em\u003e\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\n \u003ch2\u003eTheme 2: Changes in cognition affect my wellbeing\u003c/h2\u003e\n \u003cp\u003eParticipants discussed how their cognitive symptoms had a negative effect on their wellbeing. Cognitive symptoms were described as causing participants to feel frustrated, annoyed, depressed, embarrassed, stressed or misunderstood. Some participants also highlighted how cognitive changes affected their self-esteem or exacerbated existing mental health issues, highlighting the interconnected nature of HD symptoms. Participants reflected on their current wellbeing and how cognitive and behavioural symptoms would affect their wellbeing as the disease progressed.\u003c/p\u003e\n \u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003eP1: \u0026ldquo;Well, I probably would get more frustrated \u0026hellip;the stress levels would go up because I couldn\u0026rsquo;t deal with whatever the situation was that I needed to deal with.\u0026rdquo; \u0026ndash; \u003cem\u003eproblem solving\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003eP9: \u0026ldquo;It\u0026rsquo;s things that I\u0026rsquo;m losing, that I had. That is frustrating. ... I\u0026rsquo;ve always been able to concentrate, and I was a bookkeeper for 30 odd years.\u0026rdquo; \u0026ndash; \u003cem\u003econcentration\u003c/em\u003e\u003c/p\u003e\n \u003c/div\u003e\n \u003cp\u003eSome participants also discussed how the stigma they experienced because of their symptoms contributed to worse wellbeing, rather than the symptoms themselves. For example, two participants reflected on how they were often perceived as being inebriated due to communication, language, and motor changes.\u003c/p\u003e\n \u003cp\u003eP18: \u0026ldquo;Oh, yeah, important not, for people not to judge me, that I\u0026rsquo;m not drunk.\u0026rdquo;\u003c/p\u003e\n \u003cp\u003eP16: \u0026ldquo;Someone\u0026rsquo;s like, \u0026ldquo;oh c\u0026rsquo;mon mate, you\u0026rsquo;ve already had enough to drink.\u0026rdquo; When\u003c/p\u003e\n \u003cp\u003eI\u0026rsquo;ve had like, one drink.\u0026rdquo;\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec21\" class=\"Section2\"\u003e\n \u003ch2\u003eTheme 3: Changes in cognition affect my relationships\u003c/h2\u003e\n \u003cp\u003eMany participants discussed how their cognitive symptoms had changed the dynamics of their close relationships, often putting greater burden on their partners and family members. Conversely, participants also reflected on how cognitive symptoms made them more vulnerable in their relationships as they lost personal autonomy. Some noted that they had lost valued connections because of their HD and described grappling with potential future losses. Most of the participants were married or cohabitating, and as such the impact of cognitive symptoms was primarily discussed in relation to their romantic relationships; however, some participants also reflected on the impact these symptoms had or could have on their relationship with their children, grandchildren, friends, or even colleagues.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec22\" class=\"Section2\"\u003e\n \u003ch2\u003eSubtheme 3.1: Changes in cognition have affected my relationship from my loved ones\u0026rsquo; perspective\u003c/h2\u003e\n \u003cp\u003eParticipants discussed the impact of cognitive symptoms on their relationships as being from one of two perspectives; the first perspective was that cognitive decline affects their relationship from their loved one\u0026rsquo;s perspective. Cognitive symptoms increased burden for participants\u0026rsquo; loved ones and several participants felt they were no longer able to fill the same role in their loved one\u0026rsquo;s life as before.\u003c/p\u003e\n \u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003eP12: \u0026ldquo;I used to do the [planning]. [Wife] has to do that now. And I used to do all that stuff.\u0026rdquo; \u0026ndash; \u003cem\u003eplanning\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003eP7: \u0026ldquo;That\u0026rsquo;s pretty important, really to me. Because it affects not only me, but [wife]. And we have two grandsons that live with us. And I feel to some degree they rely on me.\u0026rdquo; \u0026ndash; \u003cem\u003eagitation\u003c/em\u003e\u003c/p\u003e\n \u003c/div\u003e\n \u003cp\u003eSome participants reflected that they had observed the impact of HD symptoms on their parents\u0026rsquo; relationship and described concerns that similar dynamics would occur in their own.\u003c/p\u003e\n \u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003eP4: Yeah, if that keeps going, intensifying that\u0026rsquo;s gonna probably put a bit of a- a- a strain on him [my husband] to sort of keep dragging me on to stuff, and I\u0026rsquo;ve seen it happen with my mum and dad as well\u0026hellip;\u0026rdquo; \u0026ndash; \u003cem\u003efatigue\u003c/em\u003e\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e\n \u003ch2\u003eSubtheme 3.2: Changes in cognition have affected my relationships from my perspective\u003c/h2\u003e\n \u003cp\u003eIn this subtheme, we captured participant perceptions of how cognitive symptoms made them feel more vulnerable in their relationships and their discomfort with increased reliance on others as they lost autonomy. Participants highlighted how cognitive symptoms have contributed to losing relationships and friendships in the past, and how they feel more disconnected from their loved ones who do not understand the changes they are experiencing.\u003c/p\u003e\n \u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003eP13: \u0026ldquo;You know, I don\u0026rsquo;t have a lot of friends because of the disease, drove a lot away.\u0026rdquo; \u0026ndash; \u003cem\u003eemotional lability\u003c/em\u003e\u003c/p\u003e\n \u003c/div\u003e\n \u003cp\u003eA key discussion point in multiple interviews was the role of cognitive symptoms in losing personal autonomy. Participants noted that they were either already reliant on family members or anticipated becoming more reliant on others, which was viewed negatively.\u003c/p\u003e\n \u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003eP8: \u0026ldquo;So, I don\u0026rsquo;t want to end up like him [HD family member], where I\u0026rsquo;m totally dependent on somebody to do everything for me.\u0026rdquo;\u003c/p\u003e\n \u003cp\u003eP9: \u0026ldquo;That\u0026rsquo;s probably very important for me because I just, I don\u0026rsquo;t like having to rely on people.\u0026rdquo;\u003c/p\u003e\n \u003c/div\u003e\n \u003cp\u003eSeveral participants stated that they used strategies to mitigate the impact of their symptoms to their relationships. For example, one participant stated that she was impulsive in conversations and would not ask her children about key events in their lives or would dominate conversations. To address this, she created plans with discussion topics when calling her children on the phone.\u003c/p\u003e\n \u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003eP15: \u0026ldquo;I should be able to just have these discussions\u0026hellip;with my children without having to plan anything. So, that\u0026rsquo;s been a bit\u0026hellip;of a challenge for me.\u0026rdquo; \u0026ndash; \u003cem\u003eimpulsivity\u003c/em\u003e\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eThemes produced from interviews with HD participants.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTheme\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSubtheme\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1. Changes in cognition affect my everyday activities.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1. \u003cem\u003eChanges in cognition affect my ability to work.\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2. \u003cem\u003eChanges in cognition affect my leisure activities.\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3. \u003cem\u003eChanges in cognition affect my ability to drive.\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4. \u003cem\u003eChanges in cognition affect my ability to do domestic activities.\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5. \u003cem\u003eChanges in cognition affect my finances.\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6. \u003cem\u003eChanges in cognition affect my ability to interact and socialise.\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2. Changes in cognition affect my wellbeing.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3. Changes in cognition affect my relationships.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1. \u003cem\u003eChanges in cognition have affected my relationship from my loved one\u0026rsquo;s perspective.\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2. \u003cem\u003eChanges in cognition have affected my relationship from my perspective.\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"left\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\n \u003ctable id=\"Tab5\" border=\"1\" class=\"fr-table-selection-hover\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eRepresentation of participants by theme: HD participants.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eThemes\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e% Representation\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSymptom\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eChanges in cognition affect everyday activities.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e100% (18/18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eChanges in cognition affect my ability to work.\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e72% (13/18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMemory (10/18)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eChanges in cognition affect my leisure activities.\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e78% (14/18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePsychomotor Rhythm (10/18)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eChanges in cognition affect my driving.\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e78% (14/18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSwitching Attention (5/18)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eChanges in cognition affect my domestic activities.\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e89% (16/18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProblem Solving (8/18)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eChanges in cognition affect my finances.\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39% (7/18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eImpulsivity (4/18)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eChanges in cognition affect my ability to interact and socialise.\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e89% (16/18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMemory, Processing Speed (10/18)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eChanges in cognition affect my wellbeing.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e83% (15/18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMemory (9/18)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eChanges in cognition affect my relationships.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e89% (16/18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eChanges in cognition have affected my relationship from my loved one\u0026rsquo;s perspective.\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e83% (15/18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMood, Mental Health, and Personality (6/18)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eChanges in cognition have affected my relationships from my perspective.\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e83% (15/18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAvoiding Complex Activities (5/18)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003c/div\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo our knowledge, this study is the first to systematically identify and rate individual cognitive symptoms in HD, as well as to map them to their perceived impacts using a symptom mapping methodology. Our findings align with previous lived experience research showing that cognitive decline is important and bothersome to people with HD [\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. This work adds to the growing body of literature on the lived experience of HD and will be useful to guide patient-focused clinical trial design, including the development of clinically meaningful cognitive endpoints [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eParticipants described worsened wellbeing as an impact of cognitive symptoms, aligning with existing research showing an association between cognitive decline and reduced quality of life in people living with HD [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Specifically, changes in executive function, inattention, memory, and processing speed have been associated with both diminished quality of life and increased depression in HD [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Notably, participants in our study most frequently identified memory changes as affecting their wellbeing and mental health. Memory difficulties were also consistently rated as both important and bothersome, highlighting this domain as a meaningful concept of interest from the patient perspective and priority target for future clinical trials.\u003c/p\u003e\u003cp\u003eDomestic activities, work activities, communication, driving, and managing finances were all areas that our participants reported as affected by cognitive changes, consistent with previous research [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Symptoms like memory, processing speed, switching attention, and impulsivity were viewed as relevant to these areas of life and may be important outcomes in clinical trials. Additionally, changes in psychomotor rhythm were identified as contributing to difficulties engaging in hobby or enjoyment activities. Engagement in leisure activities is protective against cognitive and functional decline [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Our findings suggest that impairments in psychomotor function contribute to reduced leisure activity engagement and therefore could be an important area to target in future clinical trials.\u003c/p\u003e\u003cp\u003ePersonal relationships are commonly affected by changes due to HD [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]; however, our study is the first to explore the impact of specific cognitive and behavioural changes to personal relationships in this population. Interestingly, participants discussed the impact on their relationships in two ways: how they felt the relationship had been affected for their loved ones, and how they felt the relationship had been affected for them. We found that people with HD primarily viewed changes in their mood, mental health, and personality as contributing to difficulties in their relationship for their loved ones as participants felt unable to fulfill emotional obligations or previous roles in their relationships. Family members of people with HD often report feeling a sense of loss for their relationship [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e] and patient mental health is a key predictor of caregiver burden, supporting our findings [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Conversely, cognitive changes such as avoiding complex activities were more frequently discussed as affecting relationships from the perspective of people with HD. Specifically, participants discussed how cognitive decline meant losing personal autonomy and needing to rely on others. Previous research identified loss of autonomy as a key area of concern for people with HD as they become gradually more reliant on both paid and gratuitous caregivers [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. Interventions that support both cognitive and behavioural or psychiatric changes are important to support both people with HD and their loved ones.\u003c/p\u003e\u003cp\u003eA final key finding from our study was that participants could view symptoms as important but not bothersome. For example, problem solving was the symptom most frequently viewed as important by participants (94.44%) but was only viewed as bothersome by 50% of our sample. The discrepancy between how important symptoms were rated versus how bothersome they actually are to daily life is consistent with previous research conducted in PD where participants identified symptoms as important due to their anticipated future impact, even when not currently bothersome [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. This finding was usually unidirectional, meaning symptoms rated as bothersome were typically also rated as important. Our findings suggest that cognitive symptoms do not necessarily need to be presently affecting everyday life for people with HD to view them as important concepts of interest. Assessing cognitive concepts of interest that are not yet bothersome in clinical trials may still be a meaningful outcome from the patient perspective. Additionally, early assessment of important symptoms will be helpful to establish when symptoms become bothersome and ensure that cognitive endpoints used in clinical trials can adequately capture the rate of symptom change over time.\u003c/p\u003e\u003cdiv id=\"Sec25\" class=\"Section2\"\u003e\u003ch2\u003eStrengths, Limitations, and Areas for Future Research\u003c/h2\u003e\u003cp\u003eA unique contribution and strength of our study design was the use of symptom mapping methodology. Symptom mapping is a novel methodology that uses card sorting to identify and delineate important symptoms from the patient perspective and has demonstrated feasibility in multiple populations, including PD [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] and asthma [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. In HD research, symptom mapping may be particularly helpful to facilitate interviews. People with HD often experience difficulties with memory recall and sustained attention [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e], making traditional interviews cognitively demanding, especially when discussing abstract concepts like cognition. Interview guidelines for HD encourage the use of prompting [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e], and symptom mapping provides a visual aid that helps maintain focus on the conversation topic and reduce the need for verbal redirection. Our study supports the feasibility of symptom mapping in this population and suggests that it may be a useful tool for future studies conducting qualitative research in HD.\u003c/p\u003e\u003cp\u003eOne limitation in our study was the use of a cross-sectional study design. We captured participant perceptions around their cognitive symptoms at a single time point and did not capture whether or how perceptions evolve with disease progression. Longitudinal research in PD suggests that there can be changes in the perceived importance of symptoms over time [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. Similarly, cross-sectional research exploring the frequency of impacts at different AD stages found differences between group perceptions [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Like PD and AD, HD is a slowly progressing disease and it is likely that as patients move through different stages of life and disease, they will have different priorities and may perceive different symptoms and impacts as more important. Understanding meaningful outcomes at different stages of progressive diseases is an important consideration for clinical trial design in the view of the FDA [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. For example, the FDA require that outcome measures used in endpoint strategies be tailored to the specified context of use [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]; that is, the outcomes assessed should be meaningful for the population under investigation and the measure should be capable of capturing changes in meaningful symptoms within the expected timeframe of the trial. Exploring longitudinal perceptions on important and bothersome symptoms and their impacts will be helpful to create fit-for-purpose outcome measures for HD clinical trial aimed at specific HD stages and over different durations.\u003c/p\u003e\u003cp\u003eAnother consideration in our study is that participants may be underreporting or underestimating symptoms and their impacts due to reduced insight, which is characteristic in HD [\u003cspan additionalcitationids=\"CR38 CR39 CR40 CR41 CR42 CR43 CR44 CR45 CR46 CR47 CR48\" citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. As such, our findings should be interpreted as a minimum estimate of symptom bothersomeness. Reduced insight into symptoms and their impact on everyday activities often leads to discrepancies between the perspective of people with HD and other people in their lives [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Patients are key stakeholders in clinical research and understanding their direct experiences is crucial for patient-focused drug development [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]; nevertheless, including family members in lived experience research is a valuable way to more accurately understand the day-to-day experience of cognitive symptoms in HD.\u003c/p\u003e\u003cp\u003eFinally, our study was completed in a small, demographically limited Caucasian sample of Australians with HD. Perceptions of illnesses and the impact illness has differs between different countries and population groups [\u003cspan additionalcitationids=\"CR52\" citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]; Therefore, our findings may not be representative of the experience of people with HD in other countries or that are part of different racial or ethnic groups. Future research should consider exploring meaningful cognitive symptoms from other diverse perspectives.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eOur study provides patient-experience data on the bothersomeness, importance, and functional impacts of different cognitive symptoms in HD. The findings from our study can be used to support the development of patient-centred intervention development, including guiding selection and development of clinically meaningful outcome measures that capture the patient experience.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMs Cali Roiboit is a recipient of the Research Training Program (RTP) scholarship funded by the Australian Government. Professor Julie Stout is the recipient of an Australian National Health and Medical Research Investigator grant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Cali Roiboit. The first draft of the manuscript was written by Cali Roiboit and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data supporting the findings of this study are available within the article and supplementary materials. Additional de-identified data may be provided on request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of Competing Interests\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMs Cali M Roiboit is a recipient of the Research Training Program (RTP) scholarship funded by the Australian Government. Professor Julie C Stout is the recipient of an Australian National Health and Medical Research Investigator grant. Professor Stout has consulted and served advisory boards for several sponsors and clinical trials over the past 20 years and is a director of a contract research organisation that facilitates the implementation of cognitive assessments in HD clinical trials. Professor Stout has been funded by the CHDI Foundation for projects aimed at developing a cognitive assessment battery for HD clinical trials. Professor Stout provides consultation services for HD clinical trials via Stout Neuropsych Pty Ltd, and is a director of Zindametrix Pty Ltd, which facilitates the implementation of the HD-CAB in clinical trials. Associate Professor Jennifer R Mammen has consulted for and/or received research support from The Michael J Fox Foundation for Parkinson\u0026rsquo;s Research, Critical Path for Parkinson\u0026rsquo;s, National Institutes of Health/NINR, Sigma Theta Tau International, and Lundbeck. Associate Professor Jamie L Adams has received research support from the Michael J. Fox Foundation for Parkinson\u0026rsquo;s Research, Critical Path for Parkinson\u0026rsquo;s, NIH/NINDS, Biogen, the Huntington Study Group, and PhotoPharmics; received compensation as a consultant/steering committee/advisory board member from the Huntington Study Group, the Parkinson Study Group, AbbVie, VisualDx, BioSensics, Sana Biotechnology, Neuron23, Lundbeck, Biohaven, and the Michael J. Fox Foundation for Parkinson\u0026rsquo;s Research; received honoraria for speaking from the Huntington Study Group, the Parkinson Study Group, and American Neurological Association. Both Associate Professors Jennifer Mammen and Jamie Adams have received research funding from the U.S. Food and Drug Administration.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Consideration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval for this study was provided by the Monash University Human Research Ethics Committee (MUHREC ID: 36930).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Participate\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll participants provided written informed consent prior to participating in any study activities.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll participants provided written informed consent for their de-identified data to be used for research purposes.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eFood, F. D. A. U. S. \u0026amp; Administration, D. FDA; [cited 2023 Jan 25]. Patient-Focused Drug Development: Collecting Comprehensive and Representative Input. (2021). Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.fda.gov/regulatory-information/search-fda-guidance-documents/patient-focused-drug-development-collecting-comprehensive-and-representative-input\u003c/span\u003e\u003cspan address=\"https://www.fda.gov/regulatory-information/search-fda-guidance-documents/patient-focused-drug-development-collecting-comprehensive-and-representative-input\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFDA. U.S. Food and Drug Administration. Patient-Focused Drug Development: Selecting, Developing, or Modifying Fit-for-Purpose Clinical Outcome Assessments. (2022). 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What matters to people with memory problems, healthy volunteers and health and social care professionals in the context of developing treatment to prevent Alzheimer\u0026rsquo;s dementia? A qualitative study. \u003cem\u003eHealth Expectat\u003c/em\u003e. \u003cb\u003e22\u003c/b\u003e, 504\u0026ndash;517 (2019).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMammen, J. R. et al. Systematic review and consensus conceptual model of meaningful symptoms and functional impacts in early Parkinson\u0026rsquo;s Disease. \u003cem\u003enpj Parkinsons Dis.\u003c/em\u003e \u003cb\u003e3\u003c/b\u003e, 65 (2025).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMammen, J. R. et al. Relative Meaningfulness and Impacts of Symptoms in People with Early-Stage Parkinson\u0026rsquo;s Disease. \u003cem\u003eJ. Parkinsons Dis.\u003c/em\u003e \u003cb\u003e13\u003c/b\u003e, 619\u0026ndash;632 (2023).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMammen, J. R. et al. 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Int.\u003c/em\u003e \u003cb\u003e35\u003c/b\u003e, 1985\u0026ndash;1993 (2015).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Cognition, Huntington’s, endpoints, lived experience","lastPublishedDoi":"10.21203/rs.3.rs-6988143/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6988143/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eCognitive symptoms contribute significantly to disability in Huntington\u0026rsquo;s disease (HD) and are important to assess in clinical trials. Little is known about what symptoms are considered personally meaningful to people with HD and how these symptoms affect everyday life. This study aimed to identify personally meaningful cognitive symptoms in people with HD and map these symptoms to their everyday impacts. We conducted semi-structured symptom mapping interviews with 18 people with HD before and after clinical motor diagnosis. Participants rated their symptoms from \u0026ldquo;Not important\u0026rdquo; to \u0026ldquo;Very or Most Important\u0026rdquo; and as \u0026ldquo;Not Present\u0026rdquo; to \u0026ldquo;Most or Very Bothersome\u0026rdquo;. Interview transcripts were analysed using Reflexive Thematic Analysis (RTA) to identify key impacts of cognitive symptoms and symptom maps were collated to characterise the frequency of important and bothersome symptoms. Altered problem solving was most frequently rated as important whereas memory changes were most frequently rated as bothersome. We identified three themes and eight subthemes from interviews which elucidated how participants feel cognitive symptoms are important for their everyday lives. Specifically, changes in cognition affected: (1) everyday activities; (2) sense of wellbeing; and (3) personal relationships. Overall, we found that cognitive symptoms were both important and bothersome from the perspective of people living with HD.\u003c/p\u003e","manuscriptTitle":"Identifying and Mapping Meaningful Cognitive Symptoms and their Impacts in Huntington’s Disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-22 01:43:48","doi":"10.21203/rs.3.rs-6988143/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"07e24f20-2b5b-4e4c-b35a-fd4a7f771d30","owner":[],"postedDate":"July 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":51660923,"name":"Health sciences/Diseases"},{"id":51660924,"name":"Health sciences/Health care"},{"id":51660925,"name":"Health sciences/Neurology"},{"id":51660926,"name":"Biological sciences/Neuroscience"},{"id":51660927,"name":"Biological sciences/Psychology"},{"id":51660928,"name":"Social science/Psychology"},{"id":51660929,"name":"Health sciences/Signs and symptoms"}],"tags":[],"updatedAt":"2025-08-12T07:53:58+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-22 01:43:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6988143","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6988143","identity":"rs-6988143","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}