A new approach to digitized cognitive monitoring: validity of the SelfCog in Huntington's disease.

Cognitive deficits represent a hallmark of neurodegenerative diseases, but evaluating their progression is complex. Most current evaluations involve lengthy paper-and-pencil tasks which are subject to learning effects dependent on the mode of response (motor or verbal), the countries' language or the examiners. To address these limitations, we hypothesized that applying neuroscience principles may offer a fruitful alternative. We thus developed the SelfCog, a digitized battery that tests motor, executive, visuospatial, language and memory functions in 15 min. All cognitive functions are tested according to the same paradigm, and a randomization algorithm provides a new test at each assessment with a constant level of difficulty. Here, we assessed its validity, reliability and sensitivity to detect decline in early-stage Huntington's disease in a prospective and international multilingual study (France, the UK and Germany). Fifty-one out of 85 participants with Huntington's disease and 40 of 52 healthy controls included at baseline were followed up for 1 year. Assessments included a comprehensive clinical assessment battery including currently standard cognitive assessments alongside the SelfCog. We estimated associations between each of the clinical assessments and SelfCog using Spearman's correlation and proneness to retest effects and sensitivity to decline through linear mixed models. Longitudinal effect sizes were estimated for each cognitive score. Voxel-based morphometry and tract-based spatial statistics analyses were conducted to assess the consistency between performance on the SelfCog and MRI 3D-T1 and diffusion-weighted imaging in a subgroup that underwent MRI at baseline and after 12 months. The SelfCog detected the decline of patients with Huntington's disease in a 1-year follow-up period with satisfactory psychometric properties. Huntington's disease patients are correctly differentiated from controls. The SelfCog showed larger effect sizes than the classical cognitive assessments. Its scores were associated with grey and white matter damage at baseline and over 1 year. Given its good performance in longitudinal analyses of the Huntington's disease cohort, it should likely become a very useful tool for measuring cognition in Huntington's disease in the future. It highlights the value of moving the field along the neuroscience principles and eventually applying them to the evaluation of all neurodegenerative diseases.

The striatum in time production: The model of Huntington's disease in longitudinal study.

The unified model of time processing suggests that the striatum is a central structure involved in all tasks that require the processing of temporal durations. Patients with Huntington's disease exhibit striatal degeneration and a deficit in time perception in interval timing tasks (i.e. for duration ranging from hundreds of milliseconds to minutes), but whether this deficit extends to time production remains unclear. In this study, we investigated whether symptomatic patients (HD, N = 101) or presymptomatic gene carriers (Pre-HD, N = 31) of Huntington's disease had a deficit in time production for durations between 4 and 10 s compared to healthy controls and whether this deficit developed over a year for patients. We found a clear deficit in temporal production for HD patients, whereas Pre-HD performed similarly to Controls. For HD patients and Pre-HD participants, task performance was correlated with grey matter volume in the amygdala and caudate, bilaterally. These results confirm that the striatum is involved in interval timing not only in perception but also in production, in accordance with the unified model of time processing. Furthermore, exploratory factor analyses on our data indicated that temporal production was associated with clinical assessments of psychomotor and executive functions. Finally, when retested twelve months later, the deficit of HD patients remained stable, although striatal degeneration was more pronounced. Thus, the simple, short and language-independent temporal production task may be a useful clinical tool to detect striatal degeneration in patients in early stages of Huntington's disease. However, its usefulness to detect presymptomatic stages or for monitoring the evolution of HD over a year seems limited.

Cognitive processes of apathy in Huntington's disease show high sensitivity to disease progression.

Background: Disease-modifying treatments for Huntington's disease (HD) are entering clinical trials: there is a pressing need for objective outcome measures of disease progression. Our previous work showed an association between 2 novel, objective cognitive tasks and apathy - a core feature of disease progression in HD. Objective: Evaluate the longitudinal validity and sensitivity of the novel Persistence and Maze tasks to assess their utility as clinical outcome measures in HD. Methods: 83 participants positive for the HD gene and 54 controls performed a battery of established and novel tools, at baseline and 12 month follow up. Results: The Maze task was found to be the most sensitive measure of change at 12 months, including the current gold-standard measure (the composite disease progression score). Conclusion: The Maze task has potential as a novel outcome measure of disease progression in HD and may have utility in other major neurodegenerative diseases.

Different depression: motivational anhedonia governs antidepressant efficacy in Huntington's disease.

Depression is more common in neurodegenerative diseases such as Huntington's disease than the general population. Antidepressant efficacy is well-established for depression within the general population: a recent meta-analysis showed serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants and mirtazapine outperformed other antidepressants. Despite the severe morbidity, antidepressant choice in Huntington's disease is based on Class IV evidence. We used complementary approaches to determine treatment choice for depression in Huntington's disease: propensity score analyses of antidepressant treatment outcome using the ENROLL-HD data set, and a dissection of the cognitive mechanisms underlying depression in Huntington's disease using a cognitive battery based on the Research Domain Criteria for Depression. Study 1 included ENROLL-HD 5486 gene-positive adult patients started on an antidepressant medication for depression. Our outcome measures were depression (Hospital Anxiety and Depression Scale or Problem Behaviours Assessment 'Depressed Mood' item) at first follow-up (primary outcome) and all follow-ups (secondary outcome). The intervention was antidepressant class. We used Svyglm&Twang in R to perform propensity scoring, using known variables (disease progression, medical comorbidity, psychiatric morbidity, sedatives, number of antidepressants, demographics and antidepressant contraindications) to determine the probability of receiving different antidepressants (propensity score) and then included the propensity score in a model of treatment efficacy. Study 2 recruited 51 gene-positive adult patients and 26 controls from the South Wales Huntington's Disease Management Service. Participants completed a motor assessment, in addition to measures of depression and apathy, followed by tasks measuring consummatory anhedonia, motivational anhedonia, learning from reward and punishment and reaction to negative outcome. We used generalised linear models to determine the association between task performance and depression scores. Study 1 showed selective serotonin reuptake inhibitors outperformed serotonin norepinephrine reuptake inhibitors on the primary outcome (P = 0.048), whilst both selective serotonin reuptake inhibitors (P = 0.00069) and bupropion (P = 0.0045) were superior to serotonin norepinephrine reuptake inhibitors on the secondary outcome. Study 2 demonstrated an association between depression score and effort for reward that was not explained by apathy. No other mechanisms were associated with depression score. We found that selective serotonin reuptake inhibitors and bupropion outperform serotonin norepinephrine reuptake inhibitors at alleviating depression in Huntington's disease. Moreover, motivational anhedonia appears the most significant mechanism underlying depression in Huntington's disease. Bupropion is improves motivational anhedonia and has a synergistic effect with selective serotonin reuptake inhibitors. This work provides the first large-scale, objective evidence to determine treatment choice for depression in Huntington's disease, and provides a model for determining antidepressant efficacy in other neurodegenerative diseases.

Cognitive decline in Huntington's disease in the Digitalized Arithmetic Task (DAT).

BACKGROUND: Efficient cognitive tasks sensitive to longitudinal deterioration in small cohorts of Huntington's disease (HD) patients are lacking in HD research. We thus developed and assessed the digitized arithmetic task (DAT), which combines inner language and executive functions in approximately 4 minutes. METHODS: We assessed the psychometric properties of DAT in three languages, across four European sites, in 77 early-stage HD patients (age: 52 ± 11 years; 27 females), and 57 controls (age: 50 ± 10, 31 females). Forty-eight HD patients and 34 controls were followed up to one year with 96 participants who underwent MRI brain imaging (HD patients = 46) at baseline and 50 participants (HD patients = 22) at one year. Linear mixed models and Pearson correlations were used to assess associations with clinical assessment. RESULTS: At baseline, HD patients were less accurate (p = 0.0002) with increased response time (p<0.0001) when compared to DAT in controls. Test-retest reliability in HD patients ranged from good to excellent for response time (range: 0.63-0.79) and from questionable to acceptable for accuracy (range: r = 0.52-0.69). Only DAT, the Mattis Dementia Rating Scale, the Symbol Digit Modalities Test, and Total Functional Capacity scores were able to detect a decline within a one-year follow-up in HD patients (all p< 0.05). In contrast with all the other cognitive tasks, DAT correlated with striatal atrophy over time (p = 0.037) but not with motor impairment. CONCLUSIONS: DAT is fast, reliable, motor-free, applicable in several languages, and able to unmask cognitive decline correlated with striatal atrophy in small cohorts of HD patients. This likely makes it a useful endpoint in future trials for HD and other neurodegenerative diseases.

Experiences of Mindfulness-Based Cognitive Therapy for Premanifest Huntington's Disease.

BACKGROUND: Psychological difficulties such as anxiety, depression, and irritability are common in Huntington's disease, even for premanifest individuals. However, very little evidence exists of psychological approaches to manage this distress. We have conducted a feasibility study with an embedded qualitative component to investigate the possibility of using mindfulness-based cognitive therapy (MBCT) and present here the findings from the qualitative data. OBJECTIVE: To investigate the experience of premanifest individuals learning and practising mindfulness through completing a course of MBCT. METHODS: Twelve premanifest individuals completed a course of MBCT and attended three follow up reunion meetings over the following year. Eleven participants agreed to be interviewed post-course and ten participants one year post-course about their experience of the course and any impact on their lives. Seven participants nominated a friend or relative (supporter) to be involved in the research, of whom six agreed to be interviewed post-course and two at one year about the impact of the course on the participants. Data were analysed using reflexive thematic analysis. RESULTS: Four themes were constructed from the data: 1) A meeting of minds: the group facilitating learning and support; 2) Mindfulness is hard, but enables more effective emotional management; 3) Mindfulness can change the relationship with self and others; and 4) Benefiting from mindfulness: the importance of persistence. CONCLUSION: The participants who completed the course found it beneficial. Some participants reported reductions in psychological distress, a greater sense of calm and better emotion regulation, with some of these positive changes also noticed by supporters. MBCT is worthy of further investigation for this population.

Objectively characterizing Huntington's disease using a novel upper limb dexterity test.

BACKGROUND: The Clinch Token Transfer Test (C3t) is a bi-manual coin transfer task that incorporates cognitive tasks to add complexity. This study explored the concurrent and convergent validity of the C3t as a simple, objective assessment of impairment that is reflective of disease severity in Huntington's, that is not reliant on clinical expertise for administration. METHODS: One-hundred-and-five participants presenting with pre-manifest (n = 16) or manifest (TFC-Stage-1 n = 39; TFC-Stage-2 n = 43; TFC-Stage-3 n = 7) Huntington's disease completed the Unified Huntington's Disease Rating Scale and the C3t at baseline. Of these, thirty-three were followed up after 12 months. Regression was used to estimate baseline individual and composite clinical scores (including cognitive, motor, and functional ability) using baseline C3t scores. Correlations between C3t and clinical scores were assessed using Spearman's R and visually inspected in relation to disease severity using scatterplots. Effect size over 12 months provided an indication of longitudinal behaviour of the C3t in relation to clinical measures. RESULTS: Baseline C3t scores predicted baseline clinical scores to within 9-13% accuracy, being associated with individual and composite clinical scores. Changes in C3t scores over 12 months were small ([Formula: see text] ≤ 0.15) and mirrored the change in clinical scores. CONCLUSION: The C3t demonstrates promise as a simple, easy to administer, objective outcome measure capable of predicting impairment that is reflective of Huntington's disease severity and offers a viable solution to support remote clinical monitoring. It may also offer utility as a screening tool for recruitment to clinical trials given preliminary indications of association with the prognostic index normed for Huntington's disease.

A feasibility investigation of mindfulness-based cognitive therapy for people with Huntington's disease.

BACKGROUND: Huntington's disease (HD) is an inherited neurodegenerative condition which affects movement, coordination and cognitive functioning. Psychological difficulties are commonly experienced; however, psychological interventions have been little researched with this population. We investigated the feasibility of conducting a randomised controlled trial (RCT) of mindfulness-based cognitive therapy (MBCT) with people with the HD genetic mutation, either pre-manifest (before onset of movement symptoms) or at an early disease stage. Specifically, we evaluated the willingness of participants to be recruited into and complete the intervention; the acceptability of the study measures in relation to completion; the feasibility of offering the standard MBCT course to people with HD; the acceptability of the intervention and the estimated effect sizes. METHODS: Participants were recruited from two UK HD centres and took part in an 8-week course of MBCT, with three reunions throughout the following year. Stress, depression, anxiety, and mindfulness were measured pre-, mid-, and post-course, at 3 months and at 1 year. Sleep, quality of life, positive affect and coping were measured pre- and post-course, at 3 months and at 1 year. Descriptive data and approximate effect sizes were calculated. Interviews were conducted post-course and at 1 year and data pertaining to the acceptability of the course were extracted. RESULTS: Twelve participants took part in two groups; all were pre-manifest. Levels of depression and anxiety were low pre-course leaving little room for improvement. Changes in stress and in some aspects of mindfulness were medium to large. The qualitative data suggested participants rated the course highly and found it helpful and no changes to the standard course were needed. Recruitment levels were below those anticipated. Most measures were found to be acceptable. CONCLUSIONS: Although the course was acceptable to those who took part, given the difficulties in recruiting and the rarity of HD, conducting an RCT of MBCT teaching groups in person does not seem feasible. However, alternative modes of course delivery (e.g. online) would allow the recruitment of people from a greater geographical area and may make an RCT feasible; this revised focus would be suitable for future feasibility studies. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02464293, registered 8 June 2015.

Association of CAG Repeats With Long-term Progression in Huntington Disease.

IMPORTANCE: In Huntington disease (HD), mutation severity is defined by the length of the CAG trinucleotide sequence, a well-known predictor of clinical onset age. The association with disease trajectory is less well characterized. Quantifiable summary measures of trajectory applicable over decades of early disease progression are lacking. An accurate model of the age-CAG association with early progression is critical to clinical trial design, informing both sample size and intervention timing. OBJECTIVE: To succinctly capture the decades-long early progression of HD and its dependence on CAG repeat length. DESIGN, SETTING, AND PARTICIPANTS: Prospective study at 4 academic HD treatment and research centers. Participants were the combined sample from the TRACK-HD and Track-On HD studies consisting of 290 gene carriers (presymptomatic to stage II), recruited from research registries at participating centers, and 153 nonbiologically related controls, generally spouses or friends. Recruitment was targeted to match a balanced, prespecified spectrum of age, CAG repeat length, and diagnostic status. In the TRACK-HD and Track-On HD studies, 13 and 5 potential participants, respectively, failed study screening. Follow-up ranged from 0 to 6 years. The study dates were January 2008 to November 2014. These analyses were performed between December 2015 and January 2019. MAIN OUTCOMES AND MEASURES: The outcome measures were principal component summary scores of motor-cognitive function and of brain volumes. The main outcome was the association of these scores with age and CAG repeat length. RESULTS: We analyzed 2065 visits from 443 participants (247 female [55.8%]; mean [SD] age, 44.4 [10.3] years). Motor-cognitive measures were highly correlated and had similar CAG repeat length-dependent associations with age. A composite summary score accounted for 67.6% of their combined variance. This score was well approximated by a score combining 3 items (total motor score, Symbol Digit Modalities Test, and Stroop word reading) from the Unified Huntington's Disease Rating Scale. For either score, initial progression age and then acceleration rate were highly CAG repeat length dependent. The acceleration continues through at least stage II disease. In contrast, 3 distinct patterns emerged among brain measures (basal ganglia, gray matter, and a combination of whole-brain, ventricular, and white matter volumes). The basal ganglia pattern showed considerable change in even the youngest participants but demonstrated minimal acceleration of loss with aging. Each clinical and brain summary score was strongly associated with the onset and rate of decline in total functional capacity. CONCLUSIONS AND RELEVANCE: Results of this study suggest that succinct summary measures of function and brain loss characterize HD progression across a wide disease span. CAG repeat length strongly predicts their decline rate. This work aids our understanding of the age and CAG repeat length-dependent association between changes in the brain and clinical manifestations of HD.

International Guidelines for the Treatment of Huntington's Disease.

The European Huntington's Disease Network (EHDN) commissioned an international task force to provide global evidence-based recommendations for everyday clinical practice for treatment of Huntington's disease (HD). The objectives of such guidelines are to standardize pharmacological, surgical and non-pharmacological treatment regimen and improve care and quality of life of patients. A formalized consensus method, adapted from the French Health Authority recommendations was used. First, national committees (French and English Experts) reviewed all studies published between 1965 and 2015 included dealing with HD symptoms classified in motor, cognitive, psychiatric, and somatic categories. Quality grades were attributed to these studies based on levels of scientific evidence. Provisional recommendations were formulated based on the strength and the accumulation of scientific evidence available. When evidence was not available, recommendations were framed based on professional agreement. A European Steering committee supervised the writing of the final recommendations through a consensus process involving two rounds of online questionnaire completion with international multidisciplinary HD health professionals. Patients' associations were invited to review the guidelines including the HD symptoms. Two hundred and nineteen statements were retained in the final guidelines. We suggest to use this adapted method associating evidence base-medicine and expert consensus to other rare diseases.

Insensitivity to loss predicts apathy in huntington's disease.

BACKGROUND: Apathy is a deficit in goal-directed behavior that significantly affects quality of life and function. It is common in Huntington's disease and other disorders affecting corticostriatal pathways. Deficits in processing of reward, altered effort, and executive dysfunction are associated with apathy in other disorders, but the cognitive processes leading to apathy in Huntington's disease remain largely unknown. A previously reported deficit in learning from losses in Huntington's disease raises the possibility of a hitherto unrecognized mechanism leading to apathy. This study's objective was to delineate the cognitive processes associated with apathy in HD. METHODS: We tested 51 Huntington's disease participants and 26 controls on a battery of novel and established measures to assess the contribution to apathy in Huntington's disease of executive function, reward value, reward-effort calculations, instrumental learning, and response to reward and loss. RESULTS: Huntington's disase participants had deficits in instrumental learning with impaired response to loss, but no evidence to suggest altered reward-related behavior or effort. We also saw an executive dysfunction contribution to apathy in Huntington's disease. DISCUSSION: We report the novel finding that apathy in Huntington's disease is associated with blunted responses to losses and impaired instrumental learning. This association is consistent with the known early degeneration of the indirect pathway and amygdala involvement in apathy in Huntington's disease, but is previously unreported in any disorder. In keeping with the comparative preservation of the ventral striatum and orbitofrontal cortex in Huntington's disease, reward valuation and reward-effort calculations did not contribute to apathy. © 2019 International Parkinson and Movement Disorder Society.

Targeting Huntingtin Expression in Patients with Huntington's Disease.

BACKGROUND: Huntington's disease is an autosomal-dominant neurodegenerative disease caused by CAG trinucleotide repeat expansion in HTT, resulting in a mutant huntingtin protein. IONIS-HTTRx (hereafter, HTTRx) is an antisense oligonucleotide designed to inhibit HTT messenger RNA and thereby reduce concentrations of mutant huntingtin. METHODS: We conducted a randomized, double-blind, multiple-ascending-dose, phase 1-2a trial involving adults with early Huntington's disease. Patients were randomly assigned in a 3:1 ratio to receive HTTRx or placebo as a bolus intrathecal administration every 4 weeks for four doses. Dose selection was guided by a preclinical model in mice and nonhuman primates that related dose level to reduction in the concentration of huntingtin. The primary end point was safety. The secondary end point was HTTRx pharmacokinetics in cerebrospinal fluid (CSF). Prespecified exploratory end points included the concentration of mutant huntingtin in CSF. RESULTS: Of the 46 patients who were enrolled in the trial, 34 were randomly assigned to receive HTTRx (at ascending dose levels of 10 to 120 mg) and 12 were randomly assigned to receive placebo. Each patient received all four doses and completed the trial. Adverse events, all of grade 1 or 2, were reported in 98% of the patients. No serious adverse events were seen in HTTRx-treated patients. There were no clinically relevant adverse changes in laboratory variables. Predose (trough) concentrations of HTTRx in CSF showed dose dependence up to doses of 60 mg. HTTRx treatment resulted in a dose-dependent reduction in the concentration of mutant huntingtin in CSF (mean percentage change from baseline, 10% in the placebo group and -20%, -25%, -28%, -42%, and -38% in the HTTRx 10-mg, 30-mg, 60-mg, 90-mg, and 120-mg dose groups, respectively). CONCLUSIONS: Intrathecal administration of HTTRx to patients with early Huntington's disease was not accompanied by serious adverse events. We observed dose-dependent reductions in concentrations of mutant huntingtin. (Funded by Ionis Pharmaceuticals and F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT02519036.).

Apathy Associated With Impaired Recognition of Happy Facial Expressions in Huntington's Disease.

OBJECTIVES: Previous research has demonstrated an association between emotion recognition and apathy in several neurological conditions involving fronto-striatal pathology, including Parkinson's disease and brain injury. In line with these findings, we aimed to determine whether apathetic participants with early Huntington's disease (HD) were more impaired on an emotion recognition task compared to non-apathetic participants and healthy controls. METHODS: We included 43 participants from the TRACK-HD study who reported apathy on the Problem Behaviours Assessment - short version (PBA-S), 67 participants who reported no apathy, and 107 controls matched for age, sex, and level of education. During their baseline TRACK-HD visit, participants completed a battery of cognitive and psychological tests including an emotion recognition task, the Hospital Depression and Anxiety Scale (HADS) and were assessed on the PBA-S. RESULTS: Compared to the non-apathetic group and the control group, the apathetic group were impaired on the recognition of happy facial expressions, after controlling for depression symptomology on the HADS and general disease progression (Unified Huntington's Disease Rating Scale total motor score). This was despite no difference between the apathetic and non-apathetic group on overall cognitive functioning assessed by a cognitive composite score. CONCLUSIONS: Impairment of the recognition of happy expressions may be part of the clinical picture of apathy in HD. While shared reliance on frontostriatal pathways may broadly explain associations between emotion recognition and apathy found across several patient groups, further work is needed to determine what relationships exist between recognition of specific emotions, distinct subtypes of apathy and underlying neuropathology. (JINS, 2019, 25, 453-461).

Obsessive-Compulsive and Perseverative Behaviors in Huntington's Disease.

BACKGROUND: Neuropsychiatric symptoms are highly prevalent in Huntington's disease (HD). However, little is known of the prevalence and course of obsessive-compulsive behaviors (OCBs) and perseverative behaviors (PBs) during the progression of the disease. OBJECTIVE: This review provides a summary of the literature on OCBs and PBs in HD gene expansion carriers (HDGECs). METHODS: Pubmed database was searched for articles on OCBs and PBs in HD up to 2017. We used search terms, all synonyms for HD, and various terms for OCBs and PBs. RESULTS: We found 5 case series and 11 original articles that describe a prevalence range of 5 to 52% for OCBs and up to 75% for PBs depending on disease stage and measurement scale used. Premanifest HDGECs report more OCBs compared to controls, and manifest HDGECs report a higher rate of OCBs compared to premanifest HDGECs. OCBs and PBs are associated with a longer disease duration and disease severity in manifest HDGECs, but decrease in the most advanced stages. When HDGECs come closer to estimated motor onset, the companion ratings on OCBs appear to be higher than the self-ratings of HDGECs. CONCLUSIONS: Both OCBs and PBs are characteristic neuropsychiatric features of HD. Perseveration is probably best distinguished from OCBs as it occurs without the individual's full awareness or insight into their presence (and the behavior may not be distressing). Although these behaviors are seldom distinguished, we conclude that differentiating OCBs from PBs in HD is beneficial for the management and treatment of these symptoms in HDGECs.

27 years of prenatal diagnosis for Huntington disease in the United Kingdom.

PURPOSE: There is little long-term, population-based data on uptake of prenatal diagnosis for Huntington disease (HD), a late-onset autosomal dominant neurodegenerative disorder, and the effect of the availability of preimplantation genetic diagnosis (PGD) on families' decisions about conventional prenatal diagnosis is not known. We report trends in prenatal diagnosis and preimplantation diagnosis for HD in the United Kingdom since services commenced. METHODS: Long-term UK-wide prospective case record-based service evaluation in 23 UK Regional Genetic Centres 1988-2015, and four UK PGD centers 2002-2015. RESULTS: From 1988 to 2015, 479 prenatal diagnoses were performed in the UK for HD. An exclusion approach was used in 150 (31%). The annual rate of HD prenatal diagnosis has remained around 18 (3.5/million) over 27 years, despite a steady increase in the use of PGD for HD since 2002. CONCLUSION: Although increasing number of couples are choosing either direct or exclusion PGD to prevent HD in their offspring, both direct and exclusion prenatal diagnosis remain important options in a health system where both PGD and prenatal diagnosis are state funded. At-risk couples should be informed of all options available to them, preferably prepregnancy.

Executive impairment is associated with unawareness of neuropsychiatric symptoms in premanifest and early Huntington's disease.

OBJECTIVE: Unawareness of neuropsychiatric symptoms appears to be common in Huntington's disease (HD), but the clinical correlates of unawareness are unclear. Identifying predictors of unawareness is important for improving diagnosis of neuropsychiatric symptoms, and cognitive impairment, specifically executive impairment, may be a potential important predictor of unawareness. The authors examined whether unawareness of neuropsychiatric symptoms is more common in early HD compared to premanifest HD, and whether executive task performance was associated with awareness, independent of demographic, motor or mood variables. METHOD: One hundred thirty-two gene-positive participants (60 premanifest and 72 early diagnosed) from the multicenter TRACK-HD study were included. Participants and their informants completed self and informant versions of the Frontal Systems Behavior Scale, which measures executive dysfunction, apathy, and disinhibition symptoms. Awareness was measured as the discrepancy between self- and informant-reports across premanifest and early HD groups. Participants' executive task performance was then assessed as a predictor of unawareness across the whole group. RESULTS: Premanifest participants reported higher levels of executive dysfunction, apathy and disinhibition than their informants, whereas early HD participants reported less executive dysfunction and apathy than their informants, indicating that unawareness is more common after diagnosis. Impaired executive task performance was related to unawareness of executive dysfunction and apathy, independent of demographic, motor and mood variables. CONCLUSIONS: Executive impairment is a useful early predictor of unawareness of neuropsychiatric symptoms in HD. Clinicians should closely monitor HD patients with executive impairment for unawareness, and consider this when assessing neuropsychiatric symptoms in HD and providing education to patients and families. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Clinical Management of Neuropsychiatric Symptoms of Huntington Disease: Expert-Based Consensus Guidelines on Agitation, Anxiety, Apathy, Psychosis and Sleep Disorders.

BACKGROUND: In clinical practice, several strategies and pharmacological options are available to treat neuropsychiatric symptoms of Huntington disease (HD). However, there is currently insufficient data for evidence-based guidelines on the management of these common symptoms. OBJECTIVE: We aimed to develop expert-based recommendations regarding the management of agitation, anxiety, apathy, psychosis, and sleep disorders. METHODS: Guideline development was based on a modified Institute of Medicine guideline process that accounted for a lack of evidence base. An international committee of 11 multidisciplinary experts proposed a series of statements regarding the description and management of each symptom. Statement assessment and validation was performed using a web-based survey tool and 84 international HD experts (neurologists and psychiatrists) who assessed the statements and indicated their level of agreement. RESULTS: High-level agreement (≥85% experts strongly agreed or agreed) was reached for 107 of the 110 statements that have been incorporated into the expert-based clinical recommendations presented herein. CONCLUSIONS: Clinical statements to guide the routine management of agitation, anxiety, apathy, psychosis, and sleep disorders in HD have been developed. Although not specifically tested in the HD population, clinical experience has shown that most of the neuropsychiatric symptoms discussed, when considered in isolation are treatable using pharmacologic and non-pharmacologic strategies developed for use in other populations. However, the management of neuropsychiatric symptoms in HD can be complex because neuropsychiatric symptoms often co-exist and treatment decisions should be adapted to cover all symptoms while limiting polypharmacy.

Apathy and atrophy of subcortical brain structures in Huntington's disease: A two-year follow-up study.

Background: Huntington's disease (HD) is characterized by motor and behavioral symptoms, and cognitive decline. HD gene carriers and their caregivers report the behavioral and cognitive symptoms as the most burdensome. Apathy is the most common behavioral symptom of HD and is related to clinical measures of disease progression, like functional capacity. However, it is unknown whether apathy is directly related to the neurodegenerative processes in HD. Objective: The aim is to investigate whether an association between atrophy of subcortical structures and apathy is present in HD, at baseline and after 2 years follow-up. Method: Volumes of 7 subcortical structures were measured using structural T1 MRI in 171 HD gene carriers of the TRACK-HD study and apathy was assessed with the Problem Behaviors Assessment-Short, at baseline and follow-up visit. At baseline, logistic regression was used to evaluate whether volumes of subcortical brain structures were associated with the presence of apathy. Linear regression was used to assess whether subcortical atrophy was associated with the degree of apathy at baseline and with an increase in severity of apathy over time. Results: At baseline, smaller volume of the thalamus showed a higher probability of the presence of apathy in HD gene carriers, but none of the subcortical structures was associated with the degree of apathy. Over time, no association between atrophy of any subcortical structures and change in degree of apathy was found. Conclusion: The presence of apathy is associated with atrophy of the thalamus in HD, suggesting that apathy has an underlying neural cause and might explain the high incidence of apathy in HD. However, no association was found between atrophy of these subcortical structures and increase in severity of apathy over a 2-year time period.

22 Years of predictive testing for Huntington's disease: the experience of the UK Huntington's Prediction Consortium.

This corrects the article DOI: 10.1038/ejhg.2016.36.