UNASSIGNED: Huntington\'s disease (HD) is a neurodegenerative disorder marked by cognitive impairment, movement abnormalities, and behavioral disturbances. The Stroop Color Word Test (SCWT) is a widely used tool to detect cognitive decline in HD. Variations in SCWT formats-horizontal (original) and vertical (Golden)-may influence performance, given HD\'s impact on cognitive and oculomotor abilities.
UNASSIGNED: This study aimed to compare the effectiveness of the horizontal and Golden vertical SCWT formats in detecting cognitive decline in HD, and to determine how performance may have been influenced by eye movement abnormalities.
UNASSIGNED: Forty-five participants with genetically confirmed HD were recruited. Both SCWT formats were administered to each participant in a counterbalanced fashion. Individual performance of all three sections on each format was standardized across 2 different norms. Raw and normed scores on each variation were compared and correlated with eye movement ratings on the Unified Huntington\'s Disease Rating Scale.
UNASSIGNED: The Golden variation elicited significantly slower responses, particularly in the Word Reading section, across two benchmark norms. Statistical analysis revealed significant performance differences between the two formats. Correlations between vertical eye movement ratings and performance on the Golden SCWT were highly significant, highlighting the impact of oculomotor coordination on cognitive assessments in HD.
UNASSIGNED: This study underscores the importance of considering test format in cognitive assessments for HD. The Golden vertical SCWT demonstrates increased sensitivity in detecting deficits in HD, possibly linked to vertical saccade abnormalities. These insights are important for improving the sensitivity of cognitive assessments and monitoring disease progression in HD research and clinical practice.

BACKGROUND: Huntington\'s disease (HD) has substantial impact on patients and carers\' lives. Managing patients in the advanced phase of HD may be challenging to primary health care professionals. The aim of this study is to elicit health care professionals\' experiences of managing the challenges with patients with advanced HD in primary health care.
METHODS: We did a qualitative study, collecting data from four focus group interviews with 22 primary health care professionals who had experience with caring for patients with HD in Norway. The data were analysed using a qualitative content analysis method, systematic text condensation.
RESULTS: We found that health care professionals who care for patients with HD in primary health care experience challenges related to patients\' behaviour, family members and caregivers, professionals\' individual competency, and the organizational context. They conveyed that successful care and management of patients with advanced HD was dependent on individuals\' competency and \"everyday tactics\", well-functioning teams, and leadership and organizational support.
CONCLUSIONS: In addition to individual competencies, including being personally suitable for the job, well-functioning primary care teams, and organization support and training is important for health care professionals\' ability to manage patients with advanced HD in primary health care.

UNASSIGNED: Direct-to-participant online reporting facilitates the conduct of clinical research by increasing access and clinically meaningful patient engagement.
UNASSIGNED: We assessed feasibility of online data collection from adults with diagnosed Huntington\'s disease (HD) who directly reported their problems and impact in their own words.
UNASSIGNED: Data were collected online from consenting United States residents who self-identified as 1) having been diagnosed with Huntington\'s disease, 2) able to ambulate independently, and 3) self-sufficient for most daily needs. Data for this pilot study were collected using the Huntington Study Group myHDstory online research platform. The Huntington Disease Patient Report of Problems (HD-PROP), an open-ended questionnaire, was used to capture verbatim bothersome problems and functional impact. Natural language processing, human-in-the-loop curation of verbatim reports involving clinical and experience experts, and machine learning classified verbatim-reports into clinically meaningful symptoms.
UNASSIGNED: All 8 questionnaires in the online pilot study were completed by 345 participants who were 60.9% men, 34.5±9.9 (mean±SD) years old, and 9.5±8.4 years since HD diagnosis. Racial self-identification was 46.4% Caucasian, 28.7% African American, 15.4% American Indian/Alaska Native, and 9.5% other. Accuracy of verbatim classification was 99%. Non-motor problems were the most frequently reported symptoms; depression and cognitive impairment were the most common.
UNASSIGNED: Online research participation was feasible for a diverse cohort of adults who self-reported an HD diagnosis and predominantly non-motor symptoms related to mood and cognition. Online research tools can help inform what bothers HD patients, identify clinically meaningful outcomes, and facilitate participation by diverse and under-represented populations.

Positron emission tomography imaging of misfolded proteins with high-affinity and selective radioligands has played a vital role in expanding our knowledge of neurodegenerative diseases such as Parkinson\'s and Alzheimer\'s disease. The pathogenesis of Huntington\'s disease, a CAG trinucleotide repeat disorder, is similarly linked to the presence of protein fibrils formed from mutant huntingtin (mHTT) protein. Development of mHTT fibril-specific radioligands has been limited by the lack of structural knowledge around mHTT and a dearth of available hit compounds for medicinal chemistry refinement. Over the past decade, the CHDI Foundation, a non-for-profit scientific management organisation has orchestrated a large-scale screen of small molecules to identify high affinity ligands of mHTT, with lead compounds now reaching clinical maturity. Here we describe the mHTT radioligands developed to date and opportunities for further improvement of this radiotracer class.

The aggregation of proteins into amyloid-like fibrils is seen in many neurodegenerative diseases. Recent years have seen much progress in our understanding of these misfolded protein inclusions, thanks to advances in techniques such as solid-state nuclear magnetic resonance (ssNMR) spectroscopy and cryogenic electron microscopy (cryo-EM). However, multiple repeat-expansion-related disorders have presented special challenges to structural elucidation. This review discusses the special role of ssNMR analysis in the study of protein aggregates associated with CAG repeat expansion disorders. In these diseases, the misfolding and aggregation affect mutant proteins with expanded polyglutamine segments. The most common disorder, Huntington\'s disease (HD), is connected to the mutation of the huntingtin protein. Since the discovery of the genetic causes for HD in the 1990s, steady progress in our understanding of the role of protein aggregation has depended on the integrative and interdisciplinary use of multiple types of structural techniques. The heterogeneous and dynamic features of polyQ protein fibrils, and in particular those formed by huntingtin N-terminal fragments, have made these aggregates into challenging targets for structural analysis. ssNMR has offered unique insights into many aspects of these amyloid-like aggregates. These include the atomic-level structure of the polyglutamine core, but also measurements of dynamics and solvent accessibility of the non-core flanking domains of these fibrils\' fuzzy coats. The obtained structural insights shed new light on pathogenic mechanisms behind this and other protein misfolding diseases.

UNASSIGNED: The Huntington\'s Disease Integrated Staging System (HD-ISS) defined disease onset using volumetric cut-offs for caudate and putamen derived from FreeSurfer 6 (FS6). The impact of the latest software update (FS7) on volumes remains unknown. The Huntington\'s Disease Young Adult Study (HD-YAS) is appropriately positioned to explore differences in FS bias when detecting early atrophy.
UNASSIGNED: Explore the relationships and differences between raw caudate and putamen volumes, calculated total intracranial volumes (cTICV), and adjusted caudate and putamen volumes, derived from FS6 and FS7, in HD-YAS.
UNASSIGNED: Images from 123 participants were segmented and quality controlled. Relationships and differences between volumes were explored using intraclass correlation (ICC) and Bland-Altman analysis.
UNASSIGNED: Across the whole cohort, ICC for raw caudate and putamen was 0.99, cTICV 0.93, adjusted caudate 0.87, and adjusted putamen 0.86 (all p < 0.0005). Compared to FS6, FS7 calculated: i) larger raw caudate (+0.8%, p < 0.00005) and putamen (+1.9%, p < 0.00005), with greater difference for larger volumes; and ii) smaller cTICV (-5.1%, p < 0.00005), with greater difference for smaller volumes. The systematic and proportional difference in cTICV was greater than raw volumes. When raw volumes were adjusted for cTICV, these effects compounded (adjusted caudate +7.0%, p < 0.00005; adjusted putamen +8.2%, p < 0.00005), with greater difference for larger volumes.
UNASSIGNED: As new software is released, it is critical that biases are explored since differences have the potential to significantly alter the findings of HD trials. Until conversion factors are defined, the HD-ISS must be applied using FS6. This should be incorporated into the HD-ISS online calculator.

OBJECTIVE: To characterize retinal and choroidal microvascular and structural changes in patients who are gene positive for mutant huntingtin protein (mHtt) with symptoms of Huntington\'s Disease (HD).
METHODS: This study is a cross-sectional comparison of patients who are gene positive for mHtt and exhibit symptoms of HD, either motor manifest or prodromal (HD group), and cognitively normal individuals without a family history of HD (control group). HD patients were diagnosed by Duke movement disorder neurologists based on the Unified Huntington\'s Disease Rating Scale (UHDRS). Fovea and optic nerve centered OCT and OCTA images were captured using Zeiss Cirrus HD-5000 with AngioPlex. Outcome metrics included central subfield thickness (CST), peripapillary retinal nerve fiber layer (pRNFL) thickness, ganglion cell-inner plexiform layer (GCIPL) thickness, and choroidal vascularity index (CVI) on OCT, and foveal avascular zone (FAZ) area, vessel density (VD), perfusion density (PD), capillary perfusion density (CPD), and capillary flux index (CFI) on OCTA. Generalized estimating equation (GEE) models were used to account for inter-eye correlation.
RESULTS: Forty-four eyes of 23 patients in the HD group and 77 eyes of 39 patients in the control group were analyzed. Average GCIPL thickness and FAZ area were decreased in the HD group compared to controls (p = 0.001, p < 0.001). No other imaging metrics were significantly different between groups.
CONCLUSIONS: Patients in the HD group had decreased GCIPL thickness and smaller FAZ area, highlighting the potential use of retinal biomarkers in detecting neurodegenerative changes in HD.

BACKGROUND: Laquinimod modulates CNS inflammatory pathways thought to be involved in the pathology of Huntington\'s disease. Studies with laquinimod in transgenic rodent models of Huntington\'s disease suggested improvements in motor function, reduction of brain volume loss, and prolonged survival. We aimed to evaluate the safety and efficacy of laquinimod in improving motor function and reducing caudate volume loss in patients with Huntington\'s disease.
METHODS: LEGATO-HD was a multicentre, double-blind, placebo-controlled, phase 2 study done at 48 sites across ten countries (Canada, Czech Republic, Germany, Italy, Netherlands, Portugal, Russia, Spain, UK, and USA). Patients aged 21-55 years with a cytosine-adenosine-guanine (CAG) repeat length of between 36 and 49 who had symptomatic Huntington\'s disease with a Unified Huntington\'s Disease Rating Scale-Total Motor Score (UHDRS-TMS) of higher than 5 and a Total Functional Capacity score of 8 or higher were randomly assigned (1:1:1:1) by centralised interactive response technology to laquinimod 0·5 mg, 1·0 mg, or 1·5 mg, or to matching placebo, administered orally once daily over 52 weeks; people involved in the randomisation had no other role in the study. Participants, investigators, and study personnel were masked to treatment assignment. The 1·5 mg group was discontinued before recruitment was finished because of cardiovascular safety concerns in multiple sclerosis studies. The primary endpoint was change from baseline in the UHDRS-TMS and the secondary endpoint was percent change in caudate volume, both comparing the 1·0 mg group with the placebo group at week 52. Primary and secondary endpoints were assessed in the full analysis set (ie, all randomised patients who received at least one dose of study drug and had at least one post-baseline UHDRS-TMS assessment). Safety measures included adverse event frequency and severity, and clinical and laboratory examinations, and were assessed in the safety analysis set (ie, all randomised patients who received at least one dose of study drug). This trial is registered with ClinicalTrials.gov, NCT02215616, and EudraCT, 2014-000418-75, and is now complete.
RESULTS: Between Oct 28, 2014, and June 19, 2018, 352 adults with Huntington\'s disease (179 [51%] men and 173 [49%] women; mean age 43·9 [SD 7·6] years and 340 [97%] White) were randomly assigned: 107 to laquinimod 0·5 mg, 107 to laquinimod 1·0 mg, 30 to laquinimod 1·5 mg, and 108 to matching placebo. Least squares mean change from baseline in UHDRS-TMS at week 52 was 1·98 (SE 0·83) in the laquinimod 1·0 mg group and 1·2 (0·82) in the placebo group (least squares mean difference 0·78 [95% CI -1·42 to 2·98], p=0·4853). Least squares mean change in caudate volume was 3·10% (SE 0·38) in the 1·0 mg group and 4·86% (0·38) in the placebo group (least squares mean difference -1·76% [95% CI -2·67 to -0·85]; p=0·0002). Laquinimod was well tolerated and there were no new safety findings. Serious adverse events were reported by eight (7%) patients on placebo, seven (7%) on laquinimod 0·5 mg, five (5%) on laquinimod 1·0 mg, and one (3%) on laquinimod 1·5 mg. There was one death, which occurred in the placebo group and was unrelated to treatment. The most frequent adverse events in all laquinimod dosed groups (0·5 mg, 1·0 mg, and 1·5 mg) were headache (38 [16%]), diarrhoea (24 [10%]), fall (18 [7%]), nasopharyngitis (20 [8%]), influenza (15 [6%]), vomiting (13 [5%]), arthralgia (11 [5%]), irritability (ten [4%]), fatigue (eight [3%]), and insomnia (eight [3%]).
CONCLUSIONS: Laquinimod did not show a significant effect on motor symptoms assessed by the UHDRS-TMS, but significantly reduced caudate volume loss compared with placebo at week 52. Huntington\'s disease has a chronic and slowly progressive course, and this study does not address whether a longer duration of laquinimod treatment could have produced detectable and meaningful changes in the clinical assessments.
BACKGROUND: Teva Pharmaceutical Industries.

BACKGROUND: Cognitive changes in Huntington\'s disease (HD) precede motor manifestations. ENROLL-HD platform includes four cognitive measures of information processing speed (IPS). Our group is eager to seek clinical markers in the life stage that is as close as possible to the age of onset (ie, the so called prodromal HD phase) because this is the best time for therapeutic interventions.
OBJECTIVE: Our study aimed to test whether cognitive scores in prodromal ENROLL-HD mutation carriers show the potential to predict the severity of motor and behavioral changes once HD became fully manifested.
METHODS: From the global ENROLL-HD cohort of 21,343 participants, we first selected a premanifest Cohort#1 (ie, subjects with Total Motor Score (TMS) <10 and Diagnostic Confidence Level (DCL) <4, N = 1.222). From this cohort, we then focused on a prodromal Cohort#2 of subjects who were ascertained to phenoconvert into manifest HD at follow-up visits (ie, subjects from 6 ≤ TMS≤9 and DCL <4 to TMS≥10 and DCL = 4, n = 206).
RESULTS: The main results of our study showed that low IPS before phenoconversion in Cohort#2 predicted the severity of motor and behavioral manifestations. By combining the four IPS cognitive measures (eg, the Categorical Verbal Fluency Test; Stroop Color Naming Test; Stroop Word Reading; Symbol Digit Modalities Test), we generated a Composite Cognition Score (CCS). The lower the CCS score the higher the TMS and the apathy scores in the same longitudinally followed-up patients after phenoconversion.
CONCLUSIONS: CCS might represent a clinical instrument to predict the prognosis of mutation carriers who are close to manifesting HD.

BACKGROUND: Palliative care focuses on improving patient and family quality of life by managing symptoms, psychosocial issues and spiritual concerns. Huntington\'s disease is a progressive neurodegenerative disorder with no current disease modifying therapy. Although the palliative care model has been postulated to be an integral part of HD care, there are gaps in knowledge about how this care should be implemented. This study aims to identify perceptions of palliative care in Huntington\'s Disease (HD), palliative care needs of people living with HD, and at what point they feel they would benefit from these resources.
METHODS: Participants volunteered from a large academic institution patient base to be involved in semi structured interviews that explored patient and caregiver experience surrounding their diagnosis, disease management, quality of life, and areas for improvement. Inclusion criteria for participants was a diagnosis of Huntington\'s disease and/or a self-identified caregiver of a person living with the disease.
RESULTS: A total of 12 independent patients, three independent caregivers, and five dyads completed the interviews. Themes identified included needs that would provide patient and caregiver centered treatment, current gaps in care, an openness and desire for palliative care, and knowledge about the desired timing of palliative care in treatment plans.
CONCLUSIONS: People living with HD and caregivers of people with HD most desire access to treatment that would focus on symptom management, availability of social resources, advanced care planning and spiritual wellbeing. The preferred timing of this intervention for most individuals would be at the onset of symptoms.