Stages Of Huntington's Disease Research Articles

Huntington’s Disease: A General Overview

This article overviews Huntington’s Disease (HD), emphasizing the development of neuroimaging biomarkers, pathogenesis discovery, and clinical treatment. The fundamental knowledge of HD includes its definition, diagnosis as an etiological subtype of neurodegenerative diseases in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), clinical neuropsychiatric symptoms, and social impact. The development of neuroimaging biomarkers is discussed with different developmental stages of HD. Mental health issues in the HD population including depression, anxiety, and psychosis were reviewed. The suicidal rate in this population is alarming, indicating the necessity to make both medical and mental health services available. Clinical treatments, including pharmacological and non-pharmacological, are overviewed with the timeline from now till the future. Recommendations are given for refining current research and future research design regarding neuroimaging biomarker exploration, early diagnosis, and potential treatment investigation. This review can provide some guidance to the development of more advanced diagnostic tools and effective treatments for this population.

Associations of inflammatory cytokines and cortisol with nonmotor features of Huntington's disease.

Huntington's disease (HD) is an inherited neurodegenerative disease involving progressive motor abnormalities, cognitive decline, and psychiatric disturbances. Depression and cognitive difficulties are among the most impactful symptoms of HD, yet the pathogenesis of these symptoms is not fully understood. HD involves low-level chronic inflammation and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which are linked to depression and cognitive impairment in non-HD populations. However, previous research on the relationships of these pathologies with depression and cognition in HD is limited and inconsistent. Fifty-three adults with the HD gene expansion (30 premanifest and 23 manifest) completed measures of depression and cognitive functioning. Forty-eight out of 53 participants provided hair samples for quantification of cortisol, and 34 participants provided blood samples for quantification of peripheral inflammatory cytokines. We examined the associations of four cytokines (interleukin [IL]-6, IL-10, IL-1β, and tumor necrosis factor [TNF]-α) and cortisol levels with depression and cognitive scores. In unadjusted models, higher levels of plasma IL-6, IL-10, and TNF-α correlated with higher depression scores, and higher levels of IL-10 and TNF-α correlated with poorer cognitive performance. After controlling for age, sex, and body mass index, only the correlations of IL-10 with depression and cognitive performance remained significant. No correlations were evident with hair cortisol. Peripheral inflammation is associated with depression symptoms and cognitive impairment in HD. Our findings suggest that interactions between the immune and nervous systems are important in HD, and highlight the potential of chronic inflammation as a therapeutic target in early stages of HD.

The pathobiology of depression in Huntington's disease: an unresolved puzzle.

Huntington's disease (HD) is an autosomal-dominant progressive neurodegenerative disease that manifests with a triad of symptoms including motor dysfunctions, cognitive deficits, and prominent neuropsychiatric symptoms, the most common of which is depression, with a prevalence between 30 and 70%. Depressive symptoms occur in all stages of HD, beginning in presymptomatic HD gene carriers, and are strongly associated with suicidal ideation and suicidality, but their relationship with other clinical dimensions in HD is controversial and the underlying pathophysiology is poorly understood. Analysis of the available literature until November 2023 concerned the prevalence, clinical manifestations, neuroimaging, transgenic models, and treatment options of HD depression. While it was believed that depression in HD is due to psychosomatic factors in view of the fatal disease, studies in transgenic models of HD demonstrated molecular changes including neurotrophic and serotonergic dysregulation and disorders of the hypothalamic-pituitary-adrenal axis inducing depression-like changes. While relevant neuropathological data are missing, recent neuroimaging studies revealed correlations between depressive symptoms and dysfunctional connectivities in the default mode network, basal ganglia and prefrontal cortex, and changes in limbic and paralimbic structures related to the basic neurodegenerative process. The impact of response to antidepressants in HD patients is controversial; selective serotonin reuptake inhibitors are superior to serotonin-norepinephrine reuptake inhibitors, while electroconvulsive therapy may be effective for pharmacotherapy resistant cases. Since compared to major depressive disorder and depression in other neurodegenerative diseases, our knowledge of the molecular basis in HD depression is limited, further studies to elucidate the heterogeneous pathogenesis in this fatal disorder are warranted.

An Overview of Specialist Services for Huntington’s Disease in the United Kingdom

Background: Huntington’s disease (HD) is a rare inherited neurodegenerative disorder characterized by complex evolving needs that change as the condition progresses. There is limited understanding about the organization of HD clinical services and their resourcing in the United Kingdom (UK). Objective: To understand the organization and resourcing of specialist HD services for people with HD (PwHD) in the UK Methods: This cross-sectional study collected quantitative data via on online survey, and qualitative data via telephone semi-structured interviews. Descriptive statistics were used to describe quantitative outcomes, and qualitative results were analyzed using content analysis. Results: A total of 31 specialist services for HD were identified. Of the 27 services that completed the online survey, 23 had an active multidisciplinary team of healthcare professionals (HCPs) and were led primarily by a mental health trust (26%) or tertiary referral hospital (26%). Specialist services offered outpatient clinics (96%), outreach in the community (74%), telemedicine (70%), inpatient beds (26%) and satellite clinics (26%). Many services indicated that their capacity (ability to see patients as often as needed with current resources) was difficult, with some services reporting more difficulty at the early or later stages of HD. Key resourcing gaps were identified with access to facilities, HCPs and referral networks. Conclusions: This research highlights the variation in organization and capacity within individual HD services as well as current resourcing and gaps in access that influence this capacity. Further research should be done to understand the impact of service organization and current resourcing gaps in access on the quality of care provided for PwHD in the UK.

An Overview of Specialist Services for Huntington's Disease in the United Kingdom.

Huntington's disease (HD) is a rare inherited neurodegenerative disorder characterized by complex evolving needs that change as the condition progresses. There is limited understanding about the organization of HD clinical services and their resourcing in the United Kingdom (UK). To understand the organization and resourcing of specialist HD services for people with HD (PwHD) in the UKMethods:This cross-sectional study collected quantitative data via on online survey, and qualitative data via telephone semi-structured interviews. Descriptive statistics were used to describe quantitative outcomes, and qualitative results were analyzed using content analysis. A total of 31 specialist services for HD were identified. Of the 27 services that completed the online survey, 23 had an active multidisciplinary team of healthcare professionals (HCPs) and were led primarily by a mental health trust (26%) or tertiary referral hospital (26%). Specialist services offered outpatient clinics (96%), outreach in the community (74%), telemedicine (70%), inpatient beds (26%) and satellite clinics (26%). Many services indicated that their capacity (ability to see patients as often as needed with current resources) was difficult, with some services reporting more difficulty at the early or later stages of HD. Key resourcing gaps were identified with access to facilities, HCPs and referral networks. This research highlights the variation in organization and capacity within individual HD services as well as current resourcing and gaps in access that influence this capacity. Further research should be done to understand the impact of service organization and current resourcing gaps in access on the quality of care provided for PwHD in the UK.

Neurophysiological hallmarks of Huntington's disease progression: an EEG and fMRI connectivity study.

Electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) can provide corroborative data on neurophysiological alterations in Huntington's disease (HD). However, the alterations in EEG and fMRI resting-state functional connectivity (rsFC), as well as their interrelations, at different stages of HD remain insufficiently investigated. This study aimed to identify neurophysiological alterations in individuals with preclinical HD (preHD) and early manifest HD (EMHD) by analyzing EEG and fMRI rsFC and examining their interrelationships. We found significant differences in EEG power between preHD individuals and healthy controls (HC), with a decrease in power in a specific frequency range at the theta-alpha border and slow alpha activity. In EMHD patients, in addition to the decrease in power in the 7-9 Hz range, a reduction in power within the classic alpha band compared to HC was observed. The fMRI analysis revealed disrupted functional connectivity in various brain networks, particularly within frontal lobe, putamen-cortical, and cortico-cerebellar networks, in individuals with the HD mutation compared to HC. The analysis of the relationship between EEG and fMRI rsFC revealed an association between decreased alpha power, observed in individuals with EMHD, and increased connectivity in large-scale brain networks. These networks include putamen-cortical, DMN-related and cortico-hippocampal circuits. Overall, the findings suggest that EEG and fMRI provide valuable information for monitoring pathological processes during the development of HD. A decrease in inhibitory control within the putamen-cortical, DMN-related and cortico-hippocampal circuits, accompanied by a reduction in alpha and theta-alpha border oscillatory activity, could potentially contribute to cognitive decline in HD.

59 Preliminary Findings of Semantic Interference in Learning and Memory Processes in Manifest Huntington’s Disease

Objective:To explore the usefulness of the Lowenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L) [Crocco et al, 2013], a novel memory-based cognitive stress test capitalizing on semantic interference, in Huntington’s Disease (HD).Participants and Methods:12 healthy adults (HA) and 14 individuals with manifest HD were administered the LASSI-L as part of an annual research visit with the UCSD Huntington’s Disease Clinical Research Center (HDCRC.) Participants in each group were well matched with regard to age and education. Individuals with manifest HD had an average MoCA score of 26, total functional capacity score of 10, and total motor score of 21 suggesting that they were in the early stages of HD. The LASSI-L examines different types of semantic interference that occur in the learning/encoding process. There are free and cued recall trials for two lists of semantically related words with certain trials specific to different aspects of semantic interference including proactive, retroactive, and failure to recover from proactive interference. T-tests for all recall trials and number of intrusions for each trial were conducted between HA and those with HD to examine whether HD renders one more prone to semantic interference in both encoding and retrieval memory processes.Results:Individuals with HD recalled fewer words on average than HA across all recall trials except for the initial free recall of the first word list. HD individuals recalled significantly fewer (∼1.5) words during the initial (t=-2.8, p=.005, Cohen’s d=2.7) and secondary (t=-2.9, p=.003, Cohen’s d=2.6) cued recall trials from the words on the first list. Individuals with HD also recalled significantly fewer words on initial free recall (t=-2.9, p=.003, Cohen’s d=2.6) and cued recall trials of the second list, with the initial cued recall (t=-2.8, p=.005, Cohen’s d=3.1) sensitive to proactive semantic interference and the second cued recall (t=-3.3, p=.001, Cohen’s d=2.6) sensitive to failure to recover from proactive semantic interference. In addition, individuals with HD also recalled significantly fewer (∼2.2) words on delayed cued recall of the first list, a measure of retroactive semantic interference, than HA (t=-4.8, p<.001, Cohen’s d=2.4). Lastly, individuals with HD recalled fewer (∼4.1) words than HA on delayed free recall of both word lists (t=-3.5, p<.001, Cohen’s d=5.9). The groups did not differ significantly with regard to number of total intrusions per trial.Conclusions:Overall, our study supports the usefulness of the LASSI-L for neuropsychological assessment of HD in clinical and research settings. In comparison to a demographically similar group of HA, individuals with manifest HD showed significant differences in frontally mediated retrieval processes as well as semantic interference processes that affect efficient encoding of novel information.

Locomotor Behavior and Memory Dysfunction Induced by 3-Nitropropionic Acid in Adult Zebrafish: Modulation of Dopaminergic Signaling.

Huntington's disease (HD) is a progressive neurodegenerative disease characterized by neuropsychiatric disturbance, cognitive impairment, and locomotor dysfunction. In the early stage (chorea) of HD, expression of dopamine D2 receptors (D2R) is reduced, whereas dopamine (DA) levels are increased. Contrary, in the late stage (bradykinesia), DA levels and the expression of D2R and dopamine D1 receptors (D1R) are reduced. 3-Nitropropionic acid (3-NPA) is a toxin that may replicate HD behavioral phenotypes and biochemical aspects. This study assessed the neurotransmitter levels, dopamine receptor gene expression, and the effect of acute exposure to quinpirole (D2R agonist) and eticlopride (D2R antagonist) in an HD model induced by 3-NPA in adult zebrafish. Quinpirole and eticlopride were acutely applied by i.p. injection in adult zebrafish after chronic treatment of 3-NPA (60mg/kg). 3-NPA treatment caused a reduction in DA, glutamate, and serotonin levels. Quinpirole reversed the bradykinesia and memory loss induced by 3-NPA. Together, these data showed that 3-NPA acts on the dopaminergic system and causes biochemical alterations similar to late-stage HD. These data reinforce the hypothesis that DA levels are linked with locomotor and memory deficits. Thus, these findings may suggest that the use of DA agonists could be a pharmacological strategy to improve the bradykinesia and memory deficits in the late-stage HD.

Generation of two human iPSC lines from dermal fibroblasts of adult- and juvenile-onset Huntington's disease patients and two healthy donors

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a mutation in the HTT gene. To generate human-induced pluripotent stem cells (hiPSCs), we used dermal fibroblasts from 1 healthy adult control (K-Pic2), 1 HD manifest patient (M-T2), 1 healthy juvenile control (jK-N1), and 1 juvenile HD patient (jHD-V1). HD stage of patients was assessed by neurological tests and donors were without comorbidities and were non-smokers. Characterization showed that the obtained hiPSCs have the same number of CAG repeats as the parental fibroblast lines, express pluripotency markers and have the ability to differentiate into all 3 germ layers.

Altered exocytosis of inhibitory synaptic vesicles at single presynaptic terminals of cultured striatal neurons in a knock-in mouse model of Huntington's disease.

Huntington's disease (HD) is a progressive dominantly inherited neurodegenerative disease caused by the expansion of a cytosine-adenine-guanine (CAG) trinucleotide repeat in the huntingtin gene, which encodes the mutant huntingtin protein containing an expanded polyglutamine tract. One of neuropathologic hallmarks of HD is selective degeneration in the striatum. Mechanisms underlying selective neurodegeneration in the striatum of HD remain elusive. Neurodegeneration is suggested to be preceded by abnormal synaptic transmission at the early stage of HD. However, how mutant huntingtin protein affects synaptic vesicle exocytosis at single presynaptic terminals of HD striatal neurons is poorly understood. Here, we measured synaptic vesicle exocytosis at single presynaptic terminals of cultured striatal neurons (mainly inhibitory neurons) in a knock-in mouse model of HD (zQ175) during electrical field stimulation using real-time imaging of FM 1-43 (a lipophilic dye). We found a significant decrease in bouton density and exocytosis of synaptic vesicles at single presynaptic terminals in cultured striatal neurons. Real-time imaging of VGAT-CypHer5E (a pH sensitive dye conjugated to an antibody against vesicular GABA transporter (VGAT)) for inhibitory synaptic vesicles revealed a reduction in bouton density and exocytosis of inhibitory synaptic vesicles at single presynaptic terminals of HD striatal neurons. Thus, our results suggest that the mutant huntingtin protein decreases bouton density and exocytosis of inhibitory synaptic vesicles at single presynaptic terminals of striatal neurons, causing impaired inhibitory synaptic transmission, eventually leading to the neurodegeneration in the striatum of HD.

Plasma neurofilament light-chain and phosphorylated tau as biomarkers of disease severity in Huntington's disease: Korean cohort data

ObjectiveTo investigate neurofilament light chain (NfL), phosphorylated tau (p-Tau) and total tau (t-Tau) as plasma markers for clinical severity in Korean Huntington's disease (HD) cohort. MethodsGenetically-confirmed 67 HD patients participated from 13 referral hospitals in South Korea. The subjects were evaluated with the Unified Huntington's Disease Rating Scale (UHDRS), total motor score (TMS) and total functional capacity (TFC), Mini-Mental Status Examination (K-MMSE), Montreal Cognitive Assessment (MoCA-K), and Beck's depression inventory (K-BDI). We measured plasma NfL, p-Tau and t-Tau concentrations using single-molecule array (SIMOA) assays. Stages of HD were classified based on UHDRS-TFC score and plasma markers were analyzed for correlation with clinical severity scales. ResultsPlasma NfL was elevated in both 6 premanifest and 61 full manifest HD patients compared to the reference value, which increased further from premanifest to manifest HD groups. The NfL level was not significantly correlated with UHDRS TMS or TFC scores in manifest HD patients. Plasma p-Tau was also elevated in HD patients (p = 0.038). The level was the highest in stage III-V HD (n = 30) group (post-hoc p < 0.05). The p-Tau was correlated with UHDRS TFC scores (adjusted p = 0.002). Plasma t-Tau neither differed among the groups nor associated with any clinical variables. ConclusionsThis study supports plasma NfL being a biomarker for initial HD manifestation in Korean cohort, and a novel suggestion of plasma p-Tau as a potential biomarker reflecting the clinical severity in full-manifest HD.

Prevalence of neurocognitive disorder in Huntington's disease using the Enroll-HD dataset.

Cognitive decline in Huntington's disease (HD) begins early in the disease course, however the reported prevalence and severity of cognitive impairment varies based on diagnostic approach. A Movement Disorders Society Task Force recently endorsed the use of standardized DSM-5-based criteria to diagnose neurocognitive disorder (NCD) in Huntington's disease. To determine the prevalence and severity of cognitive impairment across different stages of HD by applying NCD criteria (mild and major) to participant data from the Enroll-HD database. Enroll-HD participants were triaged into either premanifest (preHD), manifest or control groups. PreHD was further dichotomized into preHD near or preHD far based on predicted time to diagnosis using the scaled CAG-age product score (CAPs). Embedded cognitive performance and functional independence measures were used to determine prevalence of NCD (mild and major) for all groups. Prevalence of NCD-mild was 25.2%-38.4% for manifest HD, 22.8%-47.3% for preHD near, 11.5%-25.1% for preHD far, and 8.8%-19.1% for controls. Prevalence of NCD-major was 21.1%-57.7% for manifest HD, 0.5%-16.3% for preHD near, 0.0%-4.5% for preHD far, and 0.0%-3.0% for controls. The prevalence of NCD in HD is elevated in preHD and demonstrates a sharp rise prior to diagnosis. In manifest HD, the vast majority of participants meet criteria for NCD. These findings are important for optimizing clinical care and/or anticipating the need for supportive services.

Transcriptional and Histone Acetylation Changes Associated with CRE Elements Expose Key Factors Governing the Regulatory Circuit in the Early Stage of Huntington's Disease Models.

Huntington's disease (HD) is a disorder caused by an abnormal expansion of trinucleotide CAG repeats within the huntingtin (Htt) gene. Under normal conditions, the CREB Binding Protein interacts with CREB elements and acetylates Lysine 27 of Histone 3 to direct the expression of several genes. However, mutant Htt causes depletion of CBP, which in turn induces altered histone acetylation patterns and transcriptional deregulation. Here, we have studied a differential expression analysis and H3K27ac variation in 4- and 6-week-old R6/2 mice as a model of juvenile HD. The analysis of differential gene expression and acetylation levels were integrated into Gene Regulatory Networks revealing key regulators involved in the altered transcription cascade. Our results show changes in acetylation and gene expression levels that are related to impaired neuronal development, and key regulators clearly defined in 6-week-old mice are proposed to drive the downstream regulatory cascade in HD. Here, we describe the first approach to determine the relationship among epigenetic changes in the early stages of HD. We determined the existence of changes in pre-symptomatic stages of HD as a starting point for early onset indicators of the progression of this disease.

Understanding the Relationship Between Perseveration, Comorbid Behavioral Symptoms, Motor Decline, Functional Decline, and Self-report Accuracy in Huntington Disease Can Help Inform Clinical Practice.

Perseveration is one of the most debilitating symptoms of Huntington disease (HD). To study perseveration and its relationship to comorbid behavioral symptoms, motor decline, functional decline, and subject self-report accuracy by analyzing cross-sectional data tracking individuals who have or are at risk for HD and healthy controls (HC). We studied 96 individuals from HD families and 35 HC who were either family controls or gene negative. We used χ2 tests to compare patient demographic and survey outcomes data and to analyze the presence of obsessions and compulsions (OC), depression, and apathy relative to the presence of perseveration. Individuals with HD and perseveration had a higher presence of OC, depression, and apathy compared with individuals with HD of the same stages without perseveration (19%, 47.6%, and 47.6% vs 15%, 40%, and 25%, respectively). In addition, individuals in HD Stages 1-3 with higher motor scores (showing a later stage of disease) displayed a significantly higher rate of perseveration than the HC (P = 0.0476; P = 0.0499, respectively). The presence of an informant resulted in a significantly higher rate of perseveration reporting for individuals in HD Stages 1 and 2 (41.2% and 53.8% with informant vs 23.5% and 11.1% without informant, respectively). Perseveration was seen across all motor and functional stages for the individuals with HD, without significant differences between the different stages. Additionally, informants were beneficial to obtaining accurate patient reports of perseveration. These findings should prove useful for physician evaluation and treatment considerations.

Palliative care in advanced Huntington’s disease: a scoping review

BackgroundAs Huntington’s disease (HD) is a progressive disease for which there is no cure yet, patients in the advanced stage of HD may benefit from palliative care.ObjectiveTo review the literature focusing on palliative care in advanced stage HD, and the level of evidence.MethodsPublications between 1993 and October 29th, 2021 from 8 databases (Embase, Web of Science, Cochrane, Emcare, PsycINFO, Academic Search Premier, PMC PubMed Central and Pubmed) were included. The literature was deductively classified based on topics that are part of the definition of palliative care, or as care-related topics that emerged from the literature. Levels of evidence I (high) – V (low) were determined as defined by the Joanna Briggs Institute.ResultsOur search resulted in 333 articles, 38 of which were included. The literature covered four domains of palliative care: physical care, psychological care, spiritual care, and social care. Four other topics in the literature were: advance care planning, end-of-life needs assessments, pediatric HD care, and need for health care services. Most literature was underpinned by a low level of evidence, except for the topics on social care (Level III-V), advance care planning (Level II-V) and end-of-life needs assessments (Level II-III).ConclusionsTo deliver adequate palliative care in advanced HD, both general and HD-specific symptoms and problems need to be addressed. As the level of evidence in existing literature is low, further research is essential to improve palliative care and to meet patient’s wishes and needs.

Implications of Tau Dysregulation in Huntington's Disease and Potential for New Therapeutics.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. The disease, characterized by motor, cognitive, and psychiatric impairments, is caused by the expansion of a CAG repeat in the huntingtin gene. Despite the discovery of the mutation in 1993, no disease-modifying treatments are yet available. Understanding the molecular and cellular mechanisms involved in HD is therefore crucial for the development of novel treatments. Emerging research has found that HD might be classified as a secondary tauopathy, with the presence of tau insoluble aggregates in late HD. Increased total tau protein levels have been observed in both HD patients and animal models of HD. Tau hyperphosphorylation, the main feature of tau pathology, has also been investigated and our own published results suggest that the protein phosphorylation machinery is dysregulated in the early stages of HD in R6/1 transgenic mice, primarily in the cortex and striatum. Protein phosphorylation, catalysed by kinases, regulates numerous cellular mechanisms and has been shown to be dysregulated in other neurodegenerative disorders, including Alzheimer's disease. While it is still unclear how the mutation in the huntingtin gene leads to tau dysregulation in HD, several hypotheses have been explored. Evidence suggests that the mutant huntingtin does not directly interact with tau, but instead interacts with tau kinases, phosphatases, and proteins involved in tau alternative splicing, which could result in tau dysregulation as observed in HD. Altogether, there is increasing evidence that tau is undergoing pathological changes in HD and may be a good therapeutic target.

Informal care in Huntington's disease: Assessment of objective-subjective burden and its associated risk and protective factors.

Because of the genetic transmission of Huntington's disease (HD), informal caregivers (ICs, i.e., non-professional caregivers) might experience consecutive and/or concurrent caregiving roles to support several symptomatic relatives with HD over their life. Additionally, some ICs might be HD carriers. However, whether family burden of care is associated with specific factors in HD remains poorly studied. To provide a quantitative view of the IC burden and identify associated factors. This was a cross-sectional assessment of home-dwelling symptomatic HD individuals (from REGISTRY and Bio-HD studies) and their primary adult ICs, including the HD individual's motor, cognitive, behavioral, functional Unified Huntington's Disease Rating Scale score; IC objective burden (quantification of IC time in activities of daily living, instrumental activities of daily living and supervision, using the Resource Utilization in Dementia instrument), IC subjective burden (Zarit Burden Inventory), and ICs' social economic functioning and use of professional home care. We included 80 ICs (mean [SD] age 57 [12.9] years, 60% women) in charge of 80 individuals with early to advanced stage HD (mean age 56 [12.6] years, 51% men). The mean hours of informal care time was high: 7.3 (7.9)h/day (range 0-24); the mean professional home care was 2.8 (2.8)h/day (range 0.1-12.3). This objective burden increased with higher functional loss of the HD individual and with more severe cognitive-behavioral disorders. The mean subjective burden (35.4 [17.8], range 4-73) showed a high level since the earliest stage of HD; it was associated with HD duration (mean 9.2 [4.7] years) and with aggressive symptoms in individuals (44% of cases). The burden was partially related to the multiplex caregiving status (19%). Protective factors lowering the IC burden included the absence of financial hardship (57%), a strong social network (16%) and keeping active on the job market outside home (46%). The objective-subjective burden of ICs related to changing patterns of neuro-psychiatric symptoms and mitigating environmental characteristics around the HD individual-caregiver dyads.

Chorea Severity Change Over Time in Huntington Disease and by Huntington Disease Stage (P1-11.010)

<h3>Objective:</h3> To describe chorea severity over time in individuals with Huntington disease (HD) stratified by Total Functional Capacity (TFC). <h3>Background:</h3> Chorea, the most common motor symptom in HD, negatively affects quality of life and TFC. Addressing chorea is crucial to reduce the burden of motor symptomatology in HD. Chorea has been reported to increase initially, plateau, and potentially decrease over time; however, longitudinal data assessing chorea severity by disease stage are limited. <h3>Design/Methods:</h3> Participants were adults from Enroll-HD, a global, longitudinal, observational registry for individuals with or at risk for HD (data cut 2013–31 October 2020). The manifest population was stratified by baseline TFC score as a proxy for HD stage (TFC 7–13/stage 1–2 [early], 3–6/stage 3 [middle], 0–2/stage 4–5 [late]). Chorea severity was assessed by Total Maximal Chorea (TMC) score at baseline and at annual visits. Patients with ≥4 years of follow-up were selected for estimating chorea progression over time. <h3>Results:</h3> The manifest population was grouped by HD stage: early, n=7441; middle, n=2330; late, n=1120. Baseline TMC scores (mean [SD]) increased as HD stage progressed (early, 8.0 [4.7]; middle, 10.4 [5.8]; late, 10.6 [6.9]). For participants with ≥4 years of follow-up (n=1271), TMC scores increased over time in early-stage HD (n=963; years 1–2, 8.5 [5.0]; years 2–3, 9.1 [5.3]; years 3–4, 9.5 [5.6]), but plateaued at high levels in middle- (n=222; 10.6 [5.3]; 10.6 [6.0]; 10.1 [5.7], respectively) and late-stage HD (n=86; 10.4 [6.6]; 9.8 [6.9]; 9.7 [6.2]). <h3>Conclusions:</h3> Chorea severity increased in early-stage HD, and plateaued in middle- and late-stage HD. Chorea severity did not decrease longitudinally in any stage; however, the limited sample size for the follow-up period should be considered. These results support the need for increased awareness about the potential for persistent chorea in late-stage HD. <b>Disclosure:</b> Dr. Furr-Stimming has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Teva Pharmaceuticals. Dr. Furr-Stimming has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Michael J. Fox Foundation. Dr. Furr-Stimming has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Teva Pharmaceuticals. The institution of Dr. Furr-Stimming has received research support from Cures within Reach. The institution of Dr. Furr-Stimming has received research support from Huntington’s Disease Society of America. The institution of Dr. Furr-Stimming has received research support from Roche/Genetech. The institution of Dr. Furr-Stimming has received research support from Uniqure. The institution of Dr. Furr-Stimming has received research support from CHDI. The institution of Dr. Furr-Stimming has received research support from Huntington Study Group/Neurocrine. The institution of Dr. Furr-Stimming has received research support from NIH/University of Iowa. The institution of Dr. Furr-Stimming has received research support from Sage Therapeutics. Dr. Furr-Stimming has received publishing royalties from a publication relating to health care. Dr. Sung has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Teva Neuroscience. Dr. Sung has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech. Dr. Reshef has received personal compensation for serving as an employee of Teva. Ms. Willock has received personal compensation for serving as an employee of HCD Economics. Rinat Ribalov has received personal compensation for serving as an employee of TEVA. Miss Brighton has nothing to disclose. Dr. Leo has received personal compensation for serving as an employee of Teva Pharmaceutical Industries.

Divergent cognitive trajectories in early stage Huntington's disease: A 3-year longitudinal study.

Cognitive impairment is a central feature of Huntington's disease (HD), but it is unclear to what extent more aggressive cognitive phenotypes exist in HD among individuals with the same genetic load and equivalence in other clinical and sociodemographic variables. We included Enroll-HD study participants in early and early-mid stages of HD at baseline and with three consecutive yearly follow-ups for whom several clinical and sociodemographic as well as cognitive measures were recorded. We excluded participants with low and large CAG repeat length (CAG < 39 & > 55), with juvenile or late onset HD, and with dementia at baseline. We explored the existence of different groups according to the profile of cognitive progression using a two-step k-means cluster analysis model based on the combination of different cognitive outcomes. We identified a slow cognitive progression group of 293 participants and an aggressive progression group (F-CogHD) of 235 for which there were no differences at the baseline visit in any of the measures explored, with the exception of a slightly higher motor score in the F-CogHD group. This group showed a more pronounced annual loss of functionality and a more marked motor and psychiatric deterioration. The rate of progression of cognitive deterioration in HD is strongly variable even between patients sharing, among other variables, equivalent CAG repeat length, age, and disease duration. We can recognize at least two phenotypes that differ in terms of rate of progression. Our findings open new avenues to study additional mechanisms contributing to HD heterogeneity.

Mental health symptoms among those affected by Huntington's disease: A cross-sectional study.

Although cognitive and motor symptoms of Huntington's disease (HD) are associated with disease progression, the underlying causes of psychological symptoms are not as clearly understood. Recent evidence suggests that some mental health difficulties experienced by people with HD are shared by noncarriers within HD families. Accordingly, there is a need to evaluate potential systemic contributors to HD mental distress, to support meaningful interventions for psychological symptoms in people with HD and affected families. We used short-form Problem Behaviors Assessment mental health symptom data from the international Enroll-HD data set to characterize mental health symptoms across eight HD groups: Stages 1-5, premanifest and genotype-negative individuals, and family controls (n=8567) using chi-square analysis with post hoc comparisons. We identified that people with later-stage HD (Stages 2-5) had significantly higher apathy, obsessive-compulsiveness, and (from Stage 3) disorientation than the remaining groups at a medium effect size, and that these findings largely held across three measure administrations over time. These findings highlight the critical symptoms in manifest HD from Stage 2 onward, but also demonstrate that crucial symptoms such as depression, anxiety, and irritability are present across HD-affected groups (including noncarriers of the gene expansion). The outcomes highlight a need for specific clinical management of later-stage HD psychological symptoms, and for systemic support across affected families.