Erik van Duijn

Behavioural problems in Huntington's disease using the Problem Behaviours Assessment

OBJECTIVE To investigate behavioural problems in Huntingtons disease (HD). METHOD In 152 HD mutation carriers and a control group of 56 noncarriers at initial 50% risk, the Dutch version of the Problem Behaviours Assessment (PBA) was administered. Mutation carriers were divided into three groups according to the motor section of the Unified Huntingtons Disease Rating Scale (UHDRS): pre-(motor) symptomatic, early and advanced symptomatic subjects. The factor structure and interrater reliability of the PBA were investigated. RESULTS The clinically relevant interrater reliability of the PBA was 0.82 for severity scores and 0.73 for frequency scores. The PBA showed a three-factor solution: apathy, depression and irritability. Mutation carriers, including presymptomatic subjects, portrayed more apathy, depression and irritability than noncarriers. Early symptomatic subjects had more apathy, but not more depression or irritability, compared to presymptomatic subjects. Advanced symptomatic subjects had more apathy than early symptomatic subjects. CONCLUSIONS The PBA is a reliable and sensitive instrument. Behavioural problems occur in all stages of HD and arise before the onset of motor symptoms. Apathy is related to disease severity, whereas depression and irritability are not. The broad clinical phenotype of HD therefore requires adequate service delivery with integrated and multidisciplinary patient care.

Neuropsychiatric symptoms in a European Huntington's disease cohort (REGISTRY)

Background The majority of Huntingtons disease (HD) mutation carriers experience some psychopathology during their lifetime, varying from irritability to psychosis, but prevalences of particular symptoms vary widely due to diverse study populations in different stages of HD and the use of different assessment methods. Methods The study population consisted of 1993 HD mutation carriers from 15 European countries, all participating in the observational REGISTRY study. The behavioural section of the Unified HD Rating Scale was used to examine the prevalence and correlates of five neuropsychiatric features: depression, irritability/aggression, obsessive/compulsive behaviours, apathy and psychosis. Results Twenty-seven per cent of the participants did not have any neuropsychiatric symptom in the last month. Moderate to severe apathy occurred in 28.1% of the participants, whereas moderate to severe depression was found in 12.7%. Irritable/aggressive symptoms were present in 13.9% of the participants, and 13.2% showed obsessive/compulsive behaviours. Moderate to severe psychotic symptoms were found in only 1.2%. Only 54.9% of all participants with moderate to severe depression used antidepressants, suggesting undertreatment of depression. Obsessive/compulsive behaviours and irritability/aggression were inversely correlated with the Total Functional Capacity score, but with apathy showing the strongest inverse association. Conclusions A variety of neuropsychiatric symptoms are highly prevalent in different stages of HD in this European HD population, with apathy as the most frequent symptom. Depression, irritability/aggression and OCBs are prevalent in all stages of HD. Apathy was the key neuropsychiatric symptom occurring most often in advanced HD stages. Due to possible selection of relatively healthy participants, prevalences reported in this study might be an underestimation of prevalence in the entire HD population.

Suicidal ideation in a European Huntington's disease population.

BACKGROUND Previous studies indicate increased prevalences of suicidal ideation, suicide attempts, and completed suicide in Huntingtons disease (HD) compared with the general population. This study investigates correlates and predictors of suicidal ideation in HD. METHODS The study cohort consisted of 2106 HD mutation carriers, all participating in the REGISTRY study of the European Huntingtons Disease Network. Of the 1937 participants without suicidal ideation at baseline, 945 had one or more follow-up measurements. Participants were assessed for suicidal ideation by the behavioural subscale of the Unified Huntingtons Disease Rating Scale (UHDRS). Correlates of suicidal ideation were analyzed using logistic regression analysis and predictors were analyzed using Cox regression analysis. RESULTS At baseline, 169 (8.0%) mutation carriers endorsed suicidal ideation. Disease duration (odds ratio [OR]=0.96; 95% confidence interval [CI]: 0.9-1.0), anxiety (OR=2.14; 95%CI: 1.4-3.3), aggression (OR=2.41; 95%CI: 1.5-3.8), a previous suicide attempt (OR=3.95; 95%CI: 2.4-6.6), and a depressed mood (OR=13.71; 95%CI: 6.7-28.0) were independently correlated to suicidal ideation at baseline. The 4-year cumulative incidence of suicidal ideation was 9.9%. Longitudinally, the presence of a depressed mood (hazard ratio [HR]=2.05; 95%CI: 1.1-4.0) and use of benzodiazepines (HR=2.44; 95%CI: 1.2-5.0) at baseline were independent predictors of incident suicidal ideation, whereas a previous suicide attempt was not predictive. LIMITATIONS As suicidal ideation was assessed by only one item, and participants were a selection of all HD mutation carriers, the prevalence of suicidal ideation was likely underestimated. CONCLUSIONS Suicidal ideation in HD frequently occurs. Assessment of suicidal ideation is a priority in mutation carriers with a depressed mood and in those using benzodiazepines.

Factor analysis of behavioural symptoms in Huntington’s disease

A principal-components factor analysis was performed on behavioural data obtained from the European Huntington’s Disease Network REGISTRY study. 1690 valid assessments using the United Huntington’s Disease Rating Scale Behavioural Rating Scale were included in the analysis. This large data set confirmed previous reports of distinct behavioural patterns within Huntington’s disease comprising a depressive factor, a dysexecutive factor, an irritability factor and a psychosis factor.

Hypothalamic-pituitary-adrenal axis functioning in Huntington's disease mutation carriers compared with mutation-negative first-degree controls.

Neurodegeneration in Huntingtons disease (HD) occurs in various brain regions including the hypothalamus. In this cross-sectional study, hypothalamic-pituitary-adrenal (HPA) axis functioning was studied in 26 presymptomatic and 58 symptomatic HD mutation carriers, and 28 controls. HPA axis functioning was measured through salivary cortisol in the day curve, the cortisol awakening response (CAR), the area under the curve (AUC), the morning rise, and the dexamethasone suppression test (DST). Only the CAR was statistically different between the three groups, being explained by higher cortisol concentrations at 45 and 60 min post-awakening for presymptomatic mutation carriers compared to both symptomatic mutation carriers and controls. No differences were found for the AUC, evening and post-DST cortisol concentrations. Our study indicates a mild disturbance in morning cortisol secretion in HD mutation carriers that precedes the onset of motor symptoms.

Neuropsychiatric symptoms are very common in premanifest and early stage Huntington's Disease.

BACKGROUND Neuropsychiatric symptoms are common features of Huntingtons disease (HD). Whereas most studies have focused on cognitive and neuroimaging markers of disease progression, little is known about the prevalence of neuropsychiatric symptoms in premanifest mutation carriers far-from and close-to disease onset. METHODS We obtained neurological, cognitive and behavioral data from 230 participants classified as premanifest far-from (preHD-A) and close-to (preHD-B) motor-based disease onset, early-symptomatic (early-HD), and healthy controls. Frequency and severity of neuropsychiatric symptoms were assessed with the short Problem Behaviors Assessment for HD (PBA-s). The odds-ratio (OR) to present symptoms in the clinical range was calculated using the control group as reference. Logistic regression analysis was used to explore relationships between neuropsychiatric symptoms and medication use. RESULTS Prevalence of depression was similar in all groups. Apathy was already present in 32% of preHD-A increasing to 62% of early-HD patients. The probability of presenting apathetic symptoms was 15-88 times higher in preHD-A and preHD-B respectively than in healthy controls. Irritability and executive dysfunction were present in both preHD-B and early-HD. CONCLUSION Neuropsychiatric symptoms are highly prevalent in HD, already in the premanifest stage, with increasing prevalence of irritability, apathy and executive dysfunction closer to onset. Compared to controls, HD mutation carriers have the highest probability to develop apathy, with an increasing prevalence along disease stages. Our findings confirm the high prevalence of neuropsychiatric symptoms in HD, already many years before the onset of motor symptoms, with apathy as an early manifestation and core neuropsychiatric feature of the disease.

Huntington's disease biomarker progression profile identified by transcriptome sequencing in peripheral blood.

With several therapeutic approaches in development for Huntington’s disease, there is a need for easily accessible biomarkers to monitor disease progression and therapy response. We performed next-generation sequencing-based transcriptome analysis of total RNA from peripheral blood of 91 mutation carriers (27 presymptomatic and, 64 symptomatic) and 33 controls. Transcriptome analysis by DeepSAGE identified 167 genes significantly associated with clinical total motor score in Huntington’s disease patients. Relative to previous studies, this yielded novel genes and confirmed previously identified genes, such as H2AFY, an overlap in results that has proven difficult in the past. Pathway analysis showed enrichment of genes of the immune system and target genes of miRNAs, which are downregulated in Huntington’s disease models. Using a highly parallelized microfluidics array chip (Fluidigm), we validated 12 of the top 20 significant genes in our discovery cohort and 7 in a second independent cohort. The five genes (PROK2, ZNF238, AQP9, CYSTM1 and ANXA3) that were validated independently in both cohorts present a candidate biomarker panel for stage determination and therapeutic readout in Huntington’s disease. Finally we suggest a first empiric formula predicting total motor score from the expression levels of our biomarker panel. Our data support the view that peripheral blood is a useful source to identify biomarkers for Huntington’s disease and monitor disease progression in future clinical trials.

The effect of an e-learning supported train-the-trainer programme on implementation of suicide guidelines in mental health care

BACKGROUND Randomized studies examining the effect of training of mental health professionals in suicide prevention guidelines are scarce. We assessed whether professionals benefited from an e-learning supported Train-the-Trainer programme aimed at the application of the Dutch multidisciplinary suicide prevention guideline. METHODS 45 psychiatric departments from all over the Netherlands were clustered in pairs and randomized. In the experimental condition, all of the staff of psychiatric departments was trained by peers with an e-learning supported Train-the-Trainer programme. Guideline adherence of individual professionals was measured by means of the response to on-line video fragments. Multilevel analyses were used to establish whether variation between conditions was due to differences between individual professionals or departments. RESULTS Multilevel analysis showed that the intervention resulted in an improvement of individual professionals. At the 3 month follow-up, professionals who received the intervention showed greater guideline adherence, improved self-perceived knowledge and improved confidence as providers of care than professionals who were only exposed to traditional guideline dissemination. Subgroup analyses showed that improved guideline adherence was found among nurses but not among psychiatrists and psychologists. No significant effect of the intervention on team performance was found. LIMITATIONS The ICT environment in departments was often technically inadequate when displaying the video clips clip of the survey. This may have caused considerable drop-out and possibly introduced selection bias, as professionals who were strongly affiliated to the theme of the study might have been more likely to finish the study. CONCLUSIONS Our results support the idea that an e-learning supported Train-the-Trainer programme is an effective strategy for implementing clinical guidelines and improving care for suicidal patients. TRIAL REGISTRATION Netherlands Trial Register (NTR3092 www.trialregister.nl).

Reliability and Factor Structure of the Short Problem Behaviors Assessment for Huntington’s Disease (PBA-s) in the TRACK-HD and REGISTRY studies

The authors report the inter-rater reliability and factor structure of the Short Problem Behaviors Assessment (PBA-s), a semistructured interview to measure severity and frequency of behavioral problems in Huntingtons disease. Video recordings of 410 PBA-s interviews were rescored by an independent rater, and Cohens kappa calculated to assess inter-rater reliability. The mean kappa was 0.74 for severity and 0.76 for frequency scores, whereas weighted kappa (allowing scores to differ by 1 point) was 0.94 for severity and 0.92 for frequency scores. The results of factor analysis were consistent with previous studies using other measures. The authors conclude that the PBA-s is a reliable measure.

Anxiety in Huntington’s Disease

Anxiety is common in Huntingtons disease (HD), though it has been under-researched. The authors conducted a systematic review of anxiety in HD. The prevalence of anxiety in manifest HD ranged from 13% to 71%. No significant difference in anxiety between manifest and premanifest HD carriers was revealed. Anxiety appears to be associated with depression, suicide, irritability, quality of life (QoL), pain, illness beliefs, and coping styles but does not seem to be linked with measures of disease progression. From the few pilot studies available, interventions that show promise include olanzapine and psychosocial approaches. Improved assessment, more exploration of the nature of anxiety in HD, and evaluation of anxiety interventions are required.