Susanne Tamara de Bot

Introduction: In Huntington’s Disease (HD), clinical markers can be subjective and variable, highlighting the need for objective, quantitative biomarkers of disease state and progression. Given that neurodegeneration, iron accumulation, and neuroinflammation in the basal ganglia are associated with HD pathophysiology, this study aimed to investigate their potential as biomarkers. Methods: Eighty-two participants (25 premanifest, 20 early manifest, and 12 moderate manifest HD, and 25 controls) underwent 7T MRI. Volumes of the basal ganglia were derived from T1-weighted images, susceptibility, reflecting iron content, was quantified using quantitative susceptibility mapping, and myo-inositol (Ins/tCr) was measured using ¹H-MRS. Group differences were assessed using ANCOVAs adjusted for relevant covariates. Associations among imaging modalities, and with CAG-Age Product (CAP) score were examined using correlation and linear regression analyses.Results: Putaminal volume was lower and magnetic susceptibility was higher in the premanifest group compared with controls. In early manifest HD, caudate and pallidal volume and susceptibility were significantly lower and higher, respectively, relative to controls and premanifest HD. Ins/tCr was significantly higher in the moderate manifest group compared to all other groups. All imaging markers correlated with CAP scores. Multimodal correlation analyses showed negative correlation between regional susceptibility and volume, and total basal ganglia susceptibility correlated positively with Ins/tCr.Discussion: Iron accumulation and neurodegeneration showed alterations at similar disease stages, with putaminal changes already at the premanifest stage. Neuroinflammatory alterations were observed in the more advanced disease stage and correlated with iron deposition. The results highlight the value of multimodal imaging to capture complementary pathophysiological mechanisms.

: This analysis evaluates the feasibility and psychometric properties of daily digital cognitive assessments (DCAs) delivered on smartphones using data from the large, international Identifying Digital Endpoints to Assess FAtigue, Sleep and acTivities of daily living in Neurodegenerative disorders and Immune-mediated inflammatory diseases (IDEA-FAST) study. The data we analyse were collected from patients with neurodegenerative diseases (NDDs) and immune-mediated inflammatory diseases (IMIDs), and healthy controls (a subset who participated in all phases of the study, total N=1005) in their own homes. These data were obtained alongside data from other devices that monitored physiology, kinematics, and sleep quality. Following a baseline visit, participants were remotely monitored via three scheduled daily sessions for 6-7 days in each of 4 active assessment phases (APs). APs were separated by 6-week intervals. Daily schedules comprised a morning psychomotor vigilance task (PVT) with eDiary, afternoon session (eDiary only), and an evening digit symbol substitution task (DSST) with eDiary. We evaluated session coverage using logistic mixed effects, test-retest reliability using ICCs, disease impacts on performance using linear mixed effect ANCOVA, and familiarisation using linear mixed effects. Overall coverage was 66.7% for the PVT and 76.2% for the DSST, with no significant differences between the healthy volunteers and disease cohorts. Coverage varied significantly by time-of-day (Evening > Morning > Afternoon), and improved with age, with an interaction revealing session time-of-day affected older participants less, all p < .001. Coverage was highest in AP 1 and reduced in subsequent APs. AP-day effects on coverage interacted significantly with AP, with a modest decline over AP 1, and the pattern reversed in APs 2-4. Baseline reliability was good (> .70) for both PVT mean reaction time and DSST total correct across all cohorts, and the movement-based measure from the DSST ranged [.54, .82], with lower values in the Parkinson’s Disease and Primary Sjögren’s Syndrome cohorts. Both tasks showed significant cohort effects, with performance in IMID cohorts intermediate between healthy controls and NDD. Longitudinal analysis revealed significant familiarisation effects in DSST. This was greatest in healthy controls, with significant attenuation of these effects in disease cohorts. No effect of familiarisation was seen in the PVT. Collectively, these results support the usefulness of at-home cognitive assessment on smartphones. Brief measures of cognition can be captured remotely in disease as well as controls with good adherence and sensitivity to distinguish known patient groups from healthy controls.

Background: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease that causes motor ( e.g., chorea) and non-motor symptoms ( e.g., neurocognitive, neuropsychiatric and autonomic disturbances). Pain is a frequently reported non-motor symptom in HD, with a prevalence of around 40% in the manifest stage. Despite its high prevalence, patients with HD seem to be at risk for undertreatment of pain, as reflected by the lower analgesic use in HD in the advanced stages. The relatively low use of analgesics may result from under-recognition and inadequate assessment of pain, particularly in the advanced stages of HD. As HD progresses, pain recognition and assessment become increasingly challenging due to the emergence and progression of motor and neurocognitive symptoms. In contrast, the high prevalence of pain may be attributable to disturbances in the pain processing in terms of endogenous pain inhibition or pain facilitation. Despite the availability of specifically developed and internationally standardized experimental pain assessments to test psychometrics properties of observational pain scales and disturbances in pain processing, studies using these pain assessments in HD are too limited to permit definitive conclusions. Methods: A cross-sectional experimental study will be conducted in twenty genetically and clinically confirmed adult-onset HD patients. The primary aim is to assess the feasibility of the experimental design, which comprises three different standardized pain assessments, using a predefined feasibility checklist. Discussion: If feasibility is demonstrated, future studies using the comprehensive experimental design, including individually tailored experimental painful stimuli, are expected to provide insight into the psychometric properties of the Pain Assessment in Impaired Cognition scale (PAIC15) and the potential demonstration of altered pain processing in HD, supporting the development of improved pain management regimens. In particular, the motor symptoms ( e.g., facial chorea) of HD may have an adverse impact on the psychometric properties of the PAIC15. Trial registration: Trial registration on ClinicalTrials.gov with number: NCT06693466. Medical Research Ethics Committee Leiden, The Hague and Delft registration number: P24.014.

Presymptomatic testing (PT) for Huntington’s disease (HD) has been available for over 40 years. Individuals who opt for PT are typically at a 50% risk, though in rare cases, ‘25% at-risk individuals’ request to know their genetic status. Family planning is one of the main reasons why predictive testing is requested and with the availability of a direct test, new choices regarding reproduction emerged. In pregnancies, couples of whom the at-risk parent (ARP) does not want to know their own status may opt for direct testing in the 25% at-risk fetus. However, this option has a significant disadvantage: in 25% of cases, the gene expansion will be detected in the fetus, simultaneously revealing the ARP’s status. Nevertheless, there is a benefit to this approach that has not yet been well exploited: adding haplotyping to a normal prenatal test outcome may find the ARP (the ‘linking pin’) no longer at risk of developing HD. We have coined the term reverse haplotyping for this approach. Data from three families in which we applied this method are presented. Our aim is to raise awareness of the full potential of DNA analysis in this context.

Background: Fatigue, impaired sleep quality and daytime sleepiness, common in neurodegenerative and immune-mediated diseases, are debilitating and have serious societal and economic implications. Currently, measurement of these symptoms largely relies on self-reported questionnaires, which are burdensome for patients and lack sensitivity, granularity and reliability. Methods: Building on a preceding feasibility study and qualification advice of the European Medicines Agency, the Clinical Observational Study of the European project Identifying Digital Endpoints to Assess FAtigue, Sleep and acTivities of daily living in Neurodegenerative disorders and Immune-mediated inflammatory diseases (IDEA-FAST) investigates the relationship between digital and clinical parameters of the target concepts of fatigue, reduced sleep quality and daytime sleepiness. Results: Between 2022 and 2025, 2000 people are being recruited at 24 European sites – 500 with Parkinson's disease, 500 with inflammatory bowel disease, 200 with each of the following diseases: Huntington's disease, rheumatoid arthritis, systemic lupus erythematosus, primary Sjögren's syndrome and 200 healthy volunteers. Participants are followed over a 24-week period with four visits, each including a 1-week assessment phase at home using CE-certified digital health (including active and passive) technologies. The latter collect information on physical activity, physiology, cognition as well as social interaction and behaviour as core dimensions of the target concepts. Conclusion: This study will help to develop reliable, valid and efficient digital endpoints of fatigue, impaired sleep quality and daytime sleepiness for use in future clinical studies and trials.

Objectives: Huntington's disease (HD) is a hereditary neurodegenerative disorder characterized by a range of motor, cognitive, and psychiatric symptoms. Psychological symptoms can arise from being at risk for the disease and from its manifestation, necessitating psychological interventions to address the evolving burden, even before onset. This qualitative study explores the psychological interventions used for HD within the Dutch health care context and identifies barriers and facilitators for their implementation across the different HD disease stages. Methods: A qualitative approach using semi‐structured interviews was employed, involving 13 experienced psychologists from HD health care facilities in the Netherlands. Thematic analysis was conducted to explore the types of psychological interventions used and the facilitators and barriers affecting their implementation. Results: The study identified a range of generic and more specific interventions, with their application varying according to the stages of HD. Early interventions focus on genetic counselling and trauma therapy, while mid to late‐stage care incorporates acceptance and commitment therapy (ACT) and cognitive behavioural therapy (CBT) for managing psychological symptoms. Late‐stage interventions shift to mediated approaches involving family and care teams. Key barriers include cognitive impairments and difficulties in referring patients to other mental health care providers, while key facilitators include multidisciplinary collaboration and preventive interventions. Conclusions: Psychological interventions for HD in the Netherlands are adapted to the disease progression, emphasizing the need for stage‐specific and personalized care. The findings highlight best‐care practices and the importance of early intervention, multidisciplinary collaboration, and evaluation while identifying areas for further research and improvement in care quality.

Background: Huntington's Disease (HD) is a hereditary neurodegenerative disorder caused by a cytosine-adenine-guanine (CAG) repeat expansion (CAG > 35) in the Huntingtin ( HTT ) gene. Intermediate alleles (IAs, CAG = 27–35) are generally not associated with HD. However, IA carriers with symptoms have been reported in literature. Objective: To review the existing literature on IAs, in order to provide an overview of the clinical phenotype of IA carriers. Methods: Peer-reviewed articles published between 1993 and July 2024 from three databases (Embase, PubMed, and Web of Science) were included. Results: In case reports, a high percentage (90%) of IA carriers was reported to have symptoms (HD-related and -unrelated), or abnormalities in neuroimaging. Cohort studies also reported evidence of symptoms in IA carriers, although most cohorts did not obtain significant differences compared to controls. Conclusion: Based on this review, we argue that there is not enough evidence to draw a clear conclusion on the clinical phenotype of individuals carrying an intermediate allele of the HTT gene. Literature reports symptomatic IA carriers, but reported symptoms are non-specific and common in the general population. Additionally, the quality of the data is suboptimal, due to lack of detailed symptom descriptions, the absence of differential diagnoses, a selection bias, and a considerable publication bias towards IA carriers with symptoms. More research is needed to provide a better insight into the clinical phenotype of IA carriers.

Currently, new research projects aim to develop prognostic models that more accurately predict the age of onset and progression of disease for adult-onset autosomal dominant neurodegenerative diseases that lack disease-modifying treatments. While such predictions can be important for medical research and valuable in clinical practice, the perspectives of mutation carriers on receiving onset and progression predictions have not yet been explored. In this Dutch qualitative interview study, conducted between May and August 2023, the preferences, views, and concerns of 25 asymptomatic mutation carriers of Huntington’s Disease, Spinocerebellar Ataxia type 1, or Spinocerebellar Ataxia type 3 regarding onset and progression predictions were examined. Reasons for wanting to receive onset and progression predictions included life planning, preparing for the disease, informing family members, and reducing uncertainty and hypervigilance. Reasons against included concerns about negative psychological effects, the expectation of similar disease progression as family members, and a preference for receiving progression information at a later stage. Most participants were open towards disclosure of onset predictions but more hesitant regarding receiving progression information. The reasons expressed and the preferred predicted age ranges varied among age groups, and some differences in preferences were observed between the three diseases. These findings may guide the development and responsible implementation of such prognostic models and can support healthcare professionals in the counselling of mutation carriers of adult-onset genetic neurodegenerative diseases.

Background and objectives: The total functioning capacity (TFC) assessment has been integral to Huntington's disease (HD) research and clinical trials, measuring disease stage and progression. This study investigates the natural progression of function in HD, focusing on changes in TFC scores related to age and CAG-repeat length, and evaluates TFC's strengths and weaknesses in longitudinal studies. Methods: Using Enroll-HD platform's clinical dataset version 5, including Registry-3, we analysed data from 21,079 participants, with 16,083 having an expanded CAG repeat. Our final analysis encompassed 15,527 patients and 52,457 visits, with TFC scores ranging from 0 to 13. Results: Alluvial charts show that most individuals maintain maximum functional capacity over time. 3505 individuals experienced change in TFC scores, over the subsequent 4 years, 2224 (64.1%) experienced declining TFC scores, while 661 (18.6%) showed improvement within a year. The remaining 17.3% exhibited stable TFC scores. Age-related changes followed a specific sequence: occupation, household chores/finances, daily living, and care. Longer CAG-repeat lengths were linked to earlier functional decline, with some geographic regions showing earlier losses in specific domains. Reduced penetrance CAG-repeat groups exhibited different trajectories from full penetrance HD participants. Discussion: When we focus on those who experienced a change in TFC score, the number of HD patients with regained functional capacity is substantial, even considering interrater variability, which may influence outcome assessments in clinical trials. The TFC effectively reflects changes in functional domains as intended. Analysis of the reduced penetrance group suggests potential selection biases in seeking medical attention earlier and for reasons unrelated to HD.

Background Proper medication reconciliation (= comparing the accuracy of patient-reported medication use with pharmacy records) could prevent potentially dangerous situations such as drug–drug interactions and hospitalization. This is particularly important when patients rely on multiple medications, such as in neurodegenerative disorders like Huntington’s Disease (HD). Currently, it is unknown how often medication discrepancies occur in HD patients and which factors contribute to the discrepancies. Objective Identify prognostic factors of medication discrepancies in HD, using patient-reported medication use and local pharmacy records. Methods With 134 pre- and manifest HD patients, we performed a multivariable logistic regression analysis with medication discrepancy as dependent variable (pharmacy records as reference value) and sex, CAP score, disease status (pre- or manifest HD), number of concomitant medications taken, presence of an informal caregiver, Unified Huntington’s Disease Rating Scale-Total Functioning Capacity, unified cognitive Z-score and Problem Behaviors Assessment-short characteristic scores for depression, anxiety, and apathy as independent variables. Results Medication discrepancies were reported frequently, both in premanifest (43.2%) and manifest HD subjects (36.7%). Impaired cognition significantly predicted medication discrepancies (beta = −0.688, SE 0.27, p = 0.011). All other variables were non-significant. Conclusions Regardless of HD disease status and stage, patient self-reported medication use is not a reliable source, especially in those with impaired cognitive function. The presence of an informal caregiver and the absence of polypharmacy, depression, anxiety and apathy do not influence self-reported medication accuracy. Objective verification of medication use with HD patients’ local pharmacy is recommended. Trial registration number ICTRP-NL-OMON55123, HD-med, registered 26-Nov-2019.