Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Unmet healthcare needs, healthrelated quality of life and assistive technology for cognition in Huntington’s disease. A population-based cross-sectional study

Patients with Huntington’s disease (HD) need tailored multidisciplinary healthcare to maintain and optimize function and health-related quality of life (HRQoL). The aims of this thesis were to describe the levels and prevalence of unmet needs for healthcare and social support services in patients with HD, and to study factors associated with unmet healthcare needs, particularly the association with HRQoL. The thesis also investigates the use of assistive technology for cognition (ATC) and associations with HRQoL as a case of a supportive unmet healthcare need. Substantial unmet needs for healthcare and social support services for patients with HD were revealed. High levels of unmet needs were found at all five disease stages (I-V), but being in the middle phase of HD (disease stage III) increased the odds by 3.5 times. Higher levels of unmet needs were associated with lower HRQoL. ATC was used infrequently. An association between ATC use and HRQoL was not found, but ATC was significantly associated with functional ability. The thesis addresses an important gap in the scientific literature regarding healthcare service delivery to patients with Huntington’s disease

Unmet needs for healthcare and social support services in patients with Huntington's disease: a cross-sectional population-based study

Background In order to plan and improve provision of comprehensive care in Huntington’s disease (HD), it is critical to understand the gaps in healthcare and social support services provided to HD patients. Research has described utilization of healthcare services in HD in Europe, however, studies systematically examining needs for healthcare services and social support are lacking. This study aims to identify the level and type of met and unmet needs for health and social care services among patients with HD, and explore associated clinical and socio-demographic factors. Methods Eighty-six patients with a clinical diagnosis of HD living in the South-Eastern region of Norway were recruited. Socio-demographic and clinical characteristics were collected. The Needs and Provision Complexity Scale (NPCS) was used to assess the patients’ needs for healthcare and social services. Functional ability and disease stage was assessed using the UHDRS Functional assessment scales. In order to investigate factors determining the level of total unmet needs and the level of unmet needs for Health and personal care and Social care and support services, multivariate logistic regression models were used. Results A high level of unmet needs for health and personal care and social support services were found across all five disease stages, but most marked in disease stage III. The middle phase (disease stage III) and advanced phase (disease stages IV and V) of HD increased odds of having a high level of total unmet needs by 3.5 times and 1.4 times respectively, compared with the early phase (disease stages I and II). Similar results were found for level of unmet needs in the domain Health and personal care. Higher education tended to decrease odds of high level of unmet needs in this domain (OR = 0.48) and increase odds of higher level of unmet needs in the domain of Social care and support (OR = 1.3). Patients reporting needs on their own tended to decrease odds of having unmet needs in Health and personal care (OR = 0.57). Conclusions Needs for healthcare and social services in patients with HD should be assessed in a systematic manner, in order to provide adequate comprehensive care during the course of disease

Self-reported physical activity in people with limb-girdle muscular dystrophy and Charcot-Marie-Tooth disease in Norway

Background Physical activity is associated with positive health effects, but individuals with neuromuscular disease (NMD) may experience constraints being physically active. There is a gap in the literature on the activity level of people with NMDs, and therefore we did a study to determine the physical activity level in people with Limb-Girdle muscular dystrophy (LGMD) and Charcot-Marie-Tooth disease (CMT). Methods This study used a cross-sectional design to obtain self-reported physical activity and sitting time among individuals with LGMD and CMT who were recruited from the Norwegian registry for hereditary and congenital neuromuscular diseases. Results A total of 127 respondents who filled out questionnaires about either physical activity or sitting time were included in the analysis. Seventy (55.1%) had a diagnosis of CMT and 57 (44.9%) had a diagnosis of LGMD. Seventy-three (57.5%) respondents were female and 54 (42.5%) were male. Among the 108 respondents with available physical activity data, 44.4% reported being physically inactive. Among the 109 respondents with available sitting time data, the average sitting time was 8.6 h. Longer sitting time was associated with higher physical inactivity. Conclusion Among people with LGMD and CMT in our study, 55.6% reported being physically active. Respondents with LGMD and CMT reported longer sitting time and less physical activity compared with healthy respondents in other studies. Further research should explore variables and measures that can promote physical activity among people with neuromuscular conditions

Therapeutic use of music, dance, and rhythmic auditory cueing for patients with Huntington's disease: a systematic review

Background: Studies have assessed the therapeutic effect of music, dance, and rhythmic auditory cueing for patients with Huntington’s disease (HD). However, the synthesis of evidence in support of their positive impact on symptoms is lacking. Objective: We conducted a systematic literature review to evaluate the potential benefits of music, dance, and rhythm on the cognitive, psychiatric and motor function in patients with HD. Methods: Two- and three-keyword searches and a manual search identified medical literature published from 1999 through 2019. We considered literature that assessed outcomes of art-based rehabilitation programs or individual modalities for persons with early, middle, or advanced HD. Structured analysis was conducted using data entry tables with categories for patient health status, art methods, and outcomes. Results: Seven articles and six abstracts met eligibility criteria, of which nine evaluated art-based rehabilitation programs. Studies mainly assessed cognitive, psychiatric, and motor functions through music, dance, or rhythm modalities. Although results were conflicting, in summary improvements to motor function were dependent on disease severity and more responsive to art therapy programs than rhythm-motor synchronization. Benefits to global cognition that resulted from rhythmic training correlated with microstructural changes. Qualitative data verified a positive impact on language production, chorea, behavior, and quality of life. Conclusions: Our review has shown a potential benefit of music, dance, and rhythm for patients with HD, which is particularly important for a disease that has no cure. Art forms seemed to affect cognitive, psychiatric, motor, psychosocial, and neuroanatomical domains. However, evidence is preliminary, warranting further investigation to establish the foundation for this field

Assistive technology for cognition and health-related quality of life in Huntington’s disease

Background: Assistive technology for cognition (ATC) can be defined as external devices aimed at supporting cognitive function. Studies in neurological populations suggest that use of ATC is a promising strategy to ameliorate negative effects of cognitive impairment and improve Health-related Quality of Life (HRQoL). There is a lack of studies on the effects of ATC in HD. Objective: This study aimed to describe the use of ATC in patients with HD, and to investigate the association between ATC and HRQoL. Methods: A cross-sectional population-based study, including eighty-four patients with a clinical HD diagnosis (stages I–V). Socio-demographic and clinical data were collected, including information regarding various aspects of ATC use and an evaluation of cognitive impairment was performed. The Unified Huntington’s Disease Rating Scale (UHDRS) Total Functional Capacity scale (TFC) and the EQ-5D Visual Analogue Scale were used to evaluate functional ability and HRQoL. Descriptive analyses were conducted to describe ATC use and regression analyses to investigate associations between ATC and HRQoL. Results: Thirty-seven percent of the patients had ATC, and ATC was used most frequently in stages I-III. Information about ATC, needs evaluation and training was provided to 44%, 32.1% and 20.2% respectively. The regression analysis showed a significant association between TFC and HRQoL (β value = –0.564, p = 0.001), but there was no association between ATC and HRQoL. Conclusions: One-third of all patients used ATC, mainly those with mild to moderate cognitive impairment (stage I –III). No association between ATC and HRQoL was found. More research is needed to investigate effects of ATC in HD

Health-related quality of life and unmet healthcare needs in Huntington\u2019s disease

Abstract Background Huntington\u2019s disease (HD) is a rare neurodegenerative disorder with a prevalence of 6 per 100.000. Despite increasing research activity on HD, evidence on healthcare utilization, patients\u2019 needs for healthcare services and Health-Related Quality of Life (HRQoL) is still sparse. The present study describes HRQoL in a Norwegian cohort of HD patients, and assesses associations between unmet healthcare and social support service needs and HRQoL. Methods In this cross-sectional population-based study, 84 patients with a clinical diagnosis of HD living in the South-East of Norway completed the HRQoL questionnaire EuroQol, EQ-5D-3L. Unmet needs for healthcare and social support services were assessed by the Needs and Provision Complexity Scale (NPCS). Furthermore, functional ability was determined using the Unified Huntington\u2019s Disease Rating Scale (UHDRS) Functional assessment scales. Socio-demographics (age, gender, marital status, occupation, residence, housing situation) and clinical characteristics (disease duration, total functional capacity, comorbidity) were also recorded. Descriptive statistics were used to describe the patients\u2019 HRQoL. Regression analyses were conducted in order to investigate the relationship between unmet healthcare needs and self-reported HRQoL. Results The patients were divided across five disease stages as follows: Stage I: n \u2009=\u200912 (14%), Stage II: n \u2009=\u200922 (27%), Stage III: n \u2009=\u200919 (23%), Stage IV: n \u2009=\u200914 (16%), and Stage V: n \u2009=\u200917 (20%). Overall HRQoL was lowest in patients with advanced disease (Stages IV and V), while patients in the middle phase (Stage III) showed the most varied health profile for the five EQ-5D-3L dimensions. The regression model including level of unmet needs, clinical characteristics and demographics (age and education) accounted for 42% of variance in HRQoL. A higher level of unmet needs was associated with lower HRQoL (\u3b2 value - 0.228; p \u2009=\u20090.018) whereas a better total functional capacity corresponded to higher HRQoL (\u3b2 value 0.564; p \u2009<\u20090.001). Conclusions The study findings suggest that patients with HD do not receive healthcare services that could have a positive impact on their HRQoL

Speech and language difficulties in Huntington's disease: A qualitative study of patients’ and professional caregivers’ experiences

Background Huntington's disease (HD) is a neurodegenerative disease characterized by a triad of motor, cognitive and psychological symptoms, leading to a gradual breakdown of communication skills. Few studies have investigated how people affected by HD and their professional caregivers, for example, medical doctors, physiotherapists and nurses, experience the patients’ gradual loss of speech and language. Aims To examine communication-related experiences of patients and professional caregivers. Experiences with speech therapy and the use of augmentative and alternative communication aids (AAC) were also investigated. Methods & Procedures Seven individuals with HD and seven professional caregivers were interviewed individually, using a semi-structured interview guide. Transcripts were analysed using a conventional content analysis, and the results presented in three main categories. Outcomes & Results Most individuals with HD were aware of having communication difficulties, struggling with understanding others as well as being understood. This was confirmed by professional caregivers, who also raised ethical issues encountered when patients struggled with communication. Both groups talked about external factors (such as noise or crowded social settings) as disrupting communication, and shared recommendations on how people in general, and speech and language therapists (SLTs) in particular, could optimize communication. Very few patients had received information about communication aids, and none was using AACs. Professional caregivers underlined the importance of interdisciplinary collaborations, including SLTs, in order to optimize care. Conclusions & Implications Findings shed a light on everyday communication challenges faced by people with HD and their professional caregivers, and the lack of implementation of communication aids in this group. The dramatic impact of HD on patients’ communication skills underscores the need to include SLTs in the follow-up of this patient group, ideally from the early stages of the disease, while the patient is still capable of voicing his/her own wishes and thoughts. Future research that explores how to optimize communication and implement the use of AACs for individuals with HD is needed

Health-related quality of life and unmet healthcare needs in Huntington’s disease

Background Huntington’s disease (HD) is a rare neurodegenerative disorder with a prevalence of 6 per 100.000. Despite increasing research activity on HD, evidence on healthcare utilization, patients’ needs for healthcare services and Health-Related Quality of Life (HRQoL) is still sparse. The present study describes HRQoL in a Norwegian cohort of HD patients, and assesses associations between unmet healthcare and social support service needs and HRQoL. Methods In this cross-sectional population-based study, 84 patients with a clinical diagnosis of HD living in the South-East of Norway completed the HRQoL questionnaire EuroQol, EQ-5D-3L. Unmet needs for healthcare and social support services were assessed by the Needs and Provision Complexity Scale (NPCS). Furthermore, functional ability was determined using the Unified Huntington’s Disease Rating Scale (UHDRS) Functional assessment scales. Socio-demographics (age, gender, marital status, occupation, residence, housing situation) and clinical characteristics (disease duration, total functional capacity, comorbidity) were also recorded. Descriptive statistics were used to describe the patients’ HRQoL. Regression analyses were conducted in order to investigate the relationship between unmet healthcare needs and self-reported HRQoL. Results The patients were divided across five disease stages as follows: Stage I: n = 12 (14%), Stage II: n = 22 (27%), Stage III: n = 19 (23%), Stage IV: n = 14 (16%), and Stage V: n = 17 (20%). Overall HRQoL was lowest in patients with advanced disease (Stages IV and V), while patients in the middle phase (Stage III) showed the most varied health profile for the five EQ-5D-3L dimensions. The regression model including level of unmet needs, clinical characteristics and demographics (age and education) accounted for 42% of variance in HRQoL. A higher level of unmet needs was associated with lower HRQoL (β value - 0.228; p = 0.018) whereas a better total functional capacity corresponded to higher HRQoL (β value 0.564; p < 0.001). Conclusions The study findings suggest that patients with HD do not receive healthcare services that could have a positive impact on their HRQoL

Effects of a two-year intensive multidisciplinary rehabilitation program for patients with Huntington’s disease: a prospective intervention study

Objective: To assess effects of a two year intensive, multidisciplinary rehabilitation program for patients with early- to mid-stage Huntington’s disease. Design: A prospective intervention study. Setting: One inpatient rehabilitation center in Norway. Subjects: 10 patients, with early- to mid-stage Huntington’s disease. Interventions: A two year rehabilitation program, consisting of six admissions of three weeks each, and two evaluation stays approximately three months after the third and sixth rehabilitation admission. The program focused on physical exercise, social activities, and group/teaching sessions. Main outcome measures: Standard measures for motor function, including gait and balance, cognitive function, including MMSE and UHDRS cognitive assessment, anxiety and depression, activities of daily living (ADL), health related quality of life (QoL) and Body Mass Index (BMI). Results: Six out of ten patients completed the full program. Slight, but non-significant, decline was observed for gait and balance from baseline to the evaluation stay after two years. Non-significant improvements were observed in physical QoL, anxiety and depression, and BMI. ADL-function remained stable with no significant decline. None of the cognitive measures showed a significant decline. An analysis of individual cases revealed that four out of the six participants who completed the program sustained or improved their motor function, while motor function declined in two participants. All the six patients who completed the program reported improved or stable QoL throughout the study period. Conclusion: Our findings suggest that participation in an intensive rehabilitation program is well tolerated among motivated patients with early to mid-stage HD. The findings should be interpreted with caution due to the small sample size in this study