Background: Huntington’s disease (HD) is a genetic, neurodegenerative disease. Due to the progressive nature of HD and the absence of a cure, (health-related) quality of life ((HR)QoL) is an important topic. Several studies have investigated (HR)QoL in HD, yet a clear synthesis of the existing literature is lacking to date. We performed a systematic review on self-reported (HR)QoL, and factors and intervention effects associated with (HR)QoL in premanifest and manifest HD gene expansion carriers (pHDGECs and mHDGECs, respectively). Methods: PubMed, EMBASE, Web of Science, and PsycINFO were searched systematically from September 17th, 2021, up to August 11th, 2022. Methodological and conceptual quality of the included studies was assessed with two appraisal tools. Results: 30 out of 70 eligible articles were included. mHDGECs experienced lower (HR)QoL compared to pHDGECs and controls, whereas mixed findings were reported when compared to other neurological diseases. Several factors were associated with (HR)QoL that might contribute to lower (HR)QoL in mHDGECs, including depressive symptoms, physical and psychological symptoms, lower functional capacity, lower support, and unmet needs. Multidisciplinary rehabilitation programs and a respiratory muscle training were beneficial for (HR)QoL in mHDGECs. Discussion: (HR)QoL is experienced differently across the course of the disease. Although (HR)QoL is key for understanding the impact of HD and the effect of symptomatic treatment, there is a need to improve the methodological and conceptual shortcomings that were found in most studies, especially regarding the conceptual clarity when reporting on QoL and HRQoL. Suggestions for strengthening these shortcomings are provided in this review.

Background: A declining cognitive performance is a hallmark of Huntington’s disease (HD). The neuropsychological battery of the Unified HD Rating Scale (UHDRS'99) is commonly used for assessing cognition. However, there is a need to identify and minimize the impact of confounding factors, such as language, gender, age, and education level on cognitive decline. Objectives: Aim is to provide appropriate, normative data to allow clinicians to identify disease-associated cognitive decline in diverse HD populations by compensating for the impact of confounding factors Methods: Sample data, N = 3267 (60.5% females; mean age of 46.9 years (SD = 14.61, range 18–86) of healthy controls were used to create a normative dataset. For each neuropsychological test, a Bayesian generalized additive model with age, education, gender, and language as predictors was constructed to appropriately stratify the normative dataset. Results: With advancing age, there was a non-linear decline in cognitive performance. In addition, performance was dependent on educational levels and language in all tests. Gender had a more limited impact. Standardized scores have been calculated to ease the interpretation of an individual’s test outcome. A web-based online tool has been created to provide free access to normative data. Conclusion: For defined neuropsychological tests, the impact of gender, age, education, and language as factors confounding disease-associated cognitive decline can be minimized at the level of a single patient examination.

Introduction: Huntington’s disease (HD) is often on the margin of standard medical practice due to its low prevalence, the lack of causal treatment, and the typically long premanifest window prior to the onset of the symptoms, which contrasts with the long-lasting burden that the disease causes in affected families. Methods: To capture these socio-psychological aspects of HD and map the experiences of affected individuals, persons at risk of HD, and caregivers, we created a questionnaire using a qualitative research approach. The questionnaire containing 16 questions was conducted online for a period of three months through patient associations in Slovakia and their infrastructures. Results: In total, we received 30 responses. The survey results, in particular, indicate insufficient counselling by physicians with explicitly missing information about the possibility of preimplantation genetic diagnostic. There was also a necessity to improve comprehensive social and health care in the later stages of the disease, raise awareness of the disease in the general health community, and provide more information on ongoing clinical trials. Conclusion: The psychosocial effects, as well as the burden, can be mitigated by comprehensive genetic counselling as well as reproductive and financial guidelines and subsequent therapeutic programs to actively support patients, caregivers, children, and adolescents growing up in affected families, preferably with the help of local HD community association. Limitations: We have used online data collection to reach a wider HD community, but at the same time, we are aware that the quality of the data we would obtain through face-to-face interviews would be considerably better. Therefore, future studies need to be conducted to obtain more detailed information.

Cognitive decline is a key characteristic of Huntington’s disease (HD). This study aimed to investigate the diagnostic accuracy of a cognitive battery with six tests used by most HD research centers to assess cognitive impairment in HD. In total, 106 HD patients in different disease stages with more (HD-CD, N = 30) and less cognitive impairments (HD-NC, N = 70) and 100 healthy controls (NC) were matched by age, sex, and education and were examined using a standardized protocol including cognitive, motor, and functional assessments. One-way between-groups analysis of variance showed that controls performed significantly better than HD patients and that HD-NC significantly outperformed HD-CD patients in all cognitive tests (NC > HD-NC > HD-CD), with all Games-Howell post-hoc tests p < .001. Analyses using area under the receiver-operating characteristic curve (AUC) disclosed the diagnostic accuracy of all tests included in the battery to discriminate between NC and HD patients with AUC ranging from 0.809 to 0.862 (all p < .001) and between HD-CD and HD-NC patients with AUC ranging from 0.833 to 0.899 (all p < .001). In both analysis, Stroop Color Naming Test showed the highest discriminative potential. Additional analyses showed that cognitive deficits in all domains progressed with disease duration. Moreover, cognitive performance correlated with the severity of motor and functional impairment (all p < .001) and with the Disease Burden Score regardless of disease duration and age. Our results indicate that the cognitive battery is a suitable tool for assessing cognitive impairment in HD.

Background: The pathology of Huntington’s disease (HD) is marked by the aggregation of mutant huntingtin protein (mHTT), which results from expanded polyglutamine (polyQ) residues encoded by CAG repeats in the HTT gene. These repeats are differentially elongated in adult- and juvenile-onset HD. In striatal neurons, the mHTT disrupts cellular mechanisms such as store-operated calcium entry (SOCE), a process in which endoplasmic reticulum Ca²⁺ depletion triggers extracellular Ca²⁺ influx; however, this process can also be affected in peripheral cells. The aim of this study was to evaluate SOCE in fibroblasts derived from both HD onset patients and age-related controls. Methods: We conducted SOCE analysis in dermal fibroblasts from 12 HD patients (including adult- and juvenile-onset subtypes) and age-related healthy controls using Fura-2 AM ratiometric imaging paired with EGTA-based extracellular calcium chelation protocols. To evaluate SOCE response, we administered two SOC channel inhibitors, 6-bromo-N-(2-phenylethyl)-2,3,4,9-tetrahydro-1 H-carbazol-1-amine hydrochloride (C ₂₀ H ₂₂ BrClN ₂ ) and EVP4593, in premanifest HD fibroblasts. Results: In healthy human fibroblast lines, a decline in SOCE was observed between juvenile and adult individuals. In fibroblast lines from adult-onset HD patients (premanifest, early manifest, and manifest stages), we observed increased SOC channel activity. Conversely, juvenile-onset HD fibroblast lines exhibited reduced SOC channel activity compared to controls. Notably, SOCE dysregulation was independent of CAG repeat length in HD lines. Both SOC channel inhibitors attenuated SOCE in adult-onset HD lines. Conclusion: The mHTT upregulates SOCE in adult-onset HD fibroblasts and downregulates it in juvenile-onset HD fibroblast lines; however, SOCE levels do not correlate with the length of CAG repeats encoding mHTT. Despite opposing trends compared to age-related controls, similar levels of SOCE in both HD-onset fibroblasts were detected. Both C ₂₀ H ₂₂ BrClN ₂ and EVP4593 show potential for stabilizing SOCE in adult-onset HD. These findings suggest that dysregulated SOCE could be investigated as a peripheral target for studying pathological processes potentially associated with Huntington’s disease. Graphical

Background: In Huntington disease (HD), speech alterations are common and may emerge before onset of chorea. Slow and irregular motion rates, i.e. altered oral diadochokinesis (oDDK), are a distinctive feature. This study investigated oDDK using alternating (AMR) and sequential motion rate (SMR) tasks in manifest HD and explored the impact of antidopaminergic medications (ADM). Methods: Speech samples were acquired from 30 healthy controls (14 men; 27–78 years¸ age- and gender-matched to HD subjects) and 35 individuals with early-to-moderate HD (18 men; 22–76 years) phenotyped using standardized scales (UHDRS’99) and MR imaging to estimate disease severity. Acoustic analysis was used to quantify rate and regularity of oDDK. In an exploratory subgroup analysis, the impact of ADMs on oDKK was explored by comparing patients with and without ADMs (HD-ADM: n = 16; 8 men; 22–76 years; HD-nADM; n = 19; 10 men; 28–61 years). Results: HD patients were slower and more irregular in AMR and SMR tasks (p < 0.001) compared to controls. Analyses using area under the receiver-operating characteristic curve (AUC) showed the best characteristics for AMR (AUC = 95.0%). oDDK parameters correlated with measures of motor, cognitive and functional impairment and striatal atrophy. Patients on ADMs showed slower motion rates in both tasks (AMR p = 0.021; SMR p = 0.026), but unchanged regularity. Conclusions: Decreased AMR performance alone captured early motor impairment accurately, reflects disease severity and is ADM-sensitive. Therefore, objective acoustic analysis of AMR performance is a simple measure which may serve as read-out to monitor disease progression, e.g. in clinical trials.