Perinatal insults and neurodevelopmental disorders may impact Huntington's disease age of diagnosis

Introduction: The age of diagnosis of Huntington's disease (HD) varies among individuals with the same HTT CAG-repeat expansion size. We investigated whether early-life events, like perinatal insults or neurodevelopmental disorders, influence the diagnosis age. Methods: We used data from 13,856 participants from REGISTRY and Enroll-HD, two large international multicenter observational studies. Disease-free survival analyses of mutation carriers with an HTT CAG repeat expansion size above and including 36 were computed through Kaplan-Meier estimates of median time until an HD diagnosis. Comparisons between groups were computed using a Cox proportional hazard survival model adjusted for CAG-repeat expansion length. We also assessed whether the group effect depended on gender and the affected parent. Results: Insults in the perinatal period were associated with an earlier median age of diagnosis of 45.00 years (95%CI: 42.07–47.92) compared to 51.00 years (95%CI: 50.68–51.31) in the reference group, with a CAG-adjusted hazard ratio of 1.61 (95%CI: 1.26–2.06). Neurodevelopmental disorders were also associated with an earlier median age of diagnosis than the reference group of 47.00 years (95% CI: 43.38–50.62) with a CAG-adjusted hazard ratio of 1.42 (95%CI: 1.16–1.75). These associations did not change significantly with gender or affected parent. Conclusions: These results, derived from large observational datasets, show that perinatal insults and neurodevelopmental disorders are associated with earlier ages of diagnosis of magnitudes similar to the effects of known genetic modifiers of HD. Given their clear temporal separation, these early events may be causative of earlier HD onset, but further research is needed to prove causation

Exploring genetic factors involved in huntington disease age of onset. E2F2 as a new potential modifier gene

Age of onset (AO) of Huntington disease (HD) is mainly determined by the length of the CAG repeat expansion (CAGexp) in exon 1 of the HTT gene. Additional genetic variation has been suggested to contribute to AO, although the mechanism by which it could affect AO is presently unknown. The aim of this study is to explore the contribution of candidate genetic factors to HD AO in order to gain insight into the pathogenic mechanisms underlying this disorder. For that purpose, two AO definitions were used: the earliest age with unequivocal signs of HD (earliest AO or eAO), and the first motor symptoms age (motor AO or mAO). Multiple linear regression analyses were performed between genetic variation within 20 candidate genes and eAO or mAO, using DNA and clinical information of 253 HD patients from REGISTRY project. Gene expression analyses were carried out by RT-qPCR with an independent sample of 35 HD patients from Basque Country Hospitals. We found suggestive association signals between HD eAO and/or mAO and genetic variation within the E2F2, ATF7IP, GRIN2A, GRIN2B, LINC01559, HIP1 and GRIK2 genes. Among them, the most significant was the association between eAO and rs2742976, mapping to the promoter region of E2F2 transcription factor. Furthermore, rs2742976 T allele patient carriers exhibited significantly lower lymphocyte E2F2 gene expression, suggesting a possible implication of E2F2-dependent transcriptional activity in HD pathogenesis. Thus, E2F2 emerges as a new potential HD AO modifier factor

Cognitive decline in Huntington's disease expansion gene carriers

Background: In Huntington's Disease (HD) cognitive decline can occur before unequivocal motor signs become apparent. As cognitive decline often starts early in the course of the disease and has a progressive nature over time, cognition can be regarded as a key target for symptomatic treatment. The specific progressive profile of cognitive decline over time is unknown.Objective: The aim of this study is to quantify the progression of cognitive decline across all HD stages, from pre-motormanifest to advanced HD, and to investigate if CAG length mediates cognitive decline.Methods: In the European REGISTRY study 2669 HD expansion gene carriers underwent annual cognitive assessment. General linear mixed models were used to model the cognitive decline for each cognitive task across all disease stages. Additionally, a model was developed to evaluate the cognitive decline based on CAG length and age rather than disease stage.Results: There was significant cognitive decline on all administered tasks throughout pre-motormanifest (close to estimated disease onset) participants and the subsequent motormanifest participants from stage 1 to stage 4. Performance on the Stroop Word and Stroop Color tests additionally declined significantly across the two pre-motormanifest groups: far and close to estimated disease onset.The evaluation of cognition performance in relation to CAG length and age revealed a more rapid cognitive decline in participants with longer CAG length than participants with shorter CAG length over time.Conclusion: Cognitive performance already shows decline in pre-motormanifest HD gene expansion carriers and gradually worsens to late stage HD. HD gene expansion carriers with certain CAG length have their own cognitive profile, i.e., longer CAG length is associated with more rapid decline.</br

Huntington's Disease. Prevalence and Psychological Indicators of Pain

Background Huntington's disease (HD) is a genetic neurodegenerative condition that involves impairments in movement, cognition, and mood. Research is lacking in HD with regard to the prevalence of pain and the relationships between psychological factors and pain. The aim of this research was to investigate the prevalence of pain and identify the psychological factors associated with pain severity in people with HD. Methods This data‐mining study used data from 1474 people who participated in the European Huntington's Disease Network (EHDN) REGISTRY study. Pain severity was measured using the Medical Outcome Study 36‐item short‐form health survey. Separate ordinal regression analyses were conducted with participant‐rated and interviewer‐rated psychological measures (the Hospital Anxiety and Depression Scale–Snaith Irritability Scale and the Unified Huntington's Disease Rating Scale). The psychological factors considered were anxiety, depression, irritability, aggression, low self‐esteem, and apathy. Results The prevalence of pain in the total sample was 41% (stage I, 42%; stage II, 44%; stage III, 39%; stages IV and V, 50%). After controlling for confounding variables, pain severity was significantly associated with participant‐rated anxiety and depression. Interviewer‐rated anxiety, depression, and irritability also were significantly associated with severity of pain after controlling for confounding variables. Conclusions This research confirmed that pain is indeed an issue for people with HD, particularly during the later stages of the disease. Caregivers and health professionals should consider the possibility that people with HD might be experiencing pain, particularly if they are showing signs of anxiety, depression, or irritability

Disease stage, but not sex, predicts depression and psychological distress in Huntington's disease. A European population study

Objective: Depression and anxiety significantly affect morbidity in Huntington's disease. Mice.models of Huntington's disease have identified sex differences in mood-like behaviours that vary across disease lifespan, but this interaction has not previously been explored in humans with Huntington's disease. However, among certain medical populations, evidence of sex differences in mood across various disease stages has been found, reflecting trends among the general population that women tend to experience anxiety and depression 1.5 to 2 times more than men. The current study examined whether disease stage and sex, either separately or as an interaction term, predicted anxiety and depression in Huntington's disease. Methods: A cross-sectional study of REGISTRY data involving 453 Huntington's disease participants from 12 European countries was undertaken using the Hospital Anxiety and Depression Scale. A series of multiple regression analyses were undertaken to discover to what extent disease stage and sex predicted anxiety, depression, and general distress after controlling for a number of known predictors of mood difficulties. Results: Disease stage, but not sex, was found to predict depressive symptoms and general distress. Neither disease stage nor sex predicted anxiety. Furthermore, an interaction term computed for disease stage and sex did not contribute to the models tested. Conclusion: In terms of considering risks to developing depression and anxiety in the Huntington's disease population, practitioners may need to pay special attention to disease stage progression (but not sex differences) to enable early detection and treatment of depression (but not anxiety)

Irritability in huntington's disease: factor analysis of Snaith's irritability scale

Background Elevated levels of irritability are reported to occur in a number of neurological conditions, including Huntington's disease (HD), a genetic neurodegenerative disorder. Snaith's Irritability Scale (SIS) is used within HD research, but no psychometric evaluation of this instrument has previously been undertaken. Therefore, the current study aimed to analyze the factor structure of this scale among an HD population. Methods Exploratory and confirmatory factor analysis were used to examine the structural properties of SIS using responses from 1,264 HD gene expansion carriers, across 15 European countries, who were engaged in the REGISTRY 3 study. Results An exploratory factor analysis of a subsample of the data suggested a two‐factor interpretation of the data comprising “temper” and “self‐harm.” Eight possible models were tested for goodness of fit using confirmatory factor analysis. Two bifactor models, testing general and group factors in the structure of the scale, provided an equivocal “good” fit to the data. The first comprised a general irritability factor and two group factors (as originally proposed using SIS): outward irritability and inward irritability. The second comprised a general irritability factor and two group factors (as proposed by the exploratory factor analysis): temper and self‐harm. The findings from both models suggested that the loadings of items were higher on the general factor. Conclusions Bifactor models are proposed to best consider the structure of the SIS, with findings suggesting that an overall score should be used to measure irritability within HD populations

Cognitive decline in Huntington's disease expansion gene carriers

Background: In Huntington's Disease (HD) cognitive decline can occur before unequivocal motor signs become apparent. As cognitive decline often starts early in the course of the disease and has a progressive nature over time, cognition can be regarded as a key target for symptomatic treatment. The specific progressive profile of cognitive decline over time is unknown.Objective: The aim of this study is to quantify the progression of cognitive decline across all HD stages, from pre-motormanifest to advanced HD, and to investigate if CAG length mediates cognitive decline.Methods: In the European REGISTRY study 2669 HD expansion gene carriers underwent annual cognitive assessment. General linear mixed models were used to model the cognitive decline for each cognitive task across all disease stages. Additionally, a model was developed to evaluate the cognitive decline based on CAG length and age rather than disease stage.Results: There was significant cognitive decline on all administered tasks throughout pre-motormanifest (close to estimated disease onset) participants and the subsequent motormanifest participants from stage 1 to stage 4. Performance on the Stroop Word and Stroop Color tests additionally declined significantly across the two pre-motormanifest groups: far and close to estimated disease onset.The evaluation of cognition performance in relation to CAG length and age revealed a more rapid cognitive decline in participants with longer CAG length than participants with shorter CAG length over time.Conclusion: Cognitive performance already shows decline in pre-motormanifest HD gene expansion carriers and gradually worsens to late stage HD. HD gene expansion carriers with certain CAG length have their own cognitive profile, i.e., longer CAG length is associated with more rapid decline

Suicidal ideation and suicidal behavior according to the C-SSRS in a European cohort of Huntington's disease gene expansion carriers

Background Huntington's disease (HD) gene expansion carriers are at an increased risk of suicide, but so far, no studies have investigated the full spectrum of suicidality, including suicidal ideation, suicidal behavior and self-injurious behavior. Methods We included 1451 HD gene expansion carriers (age 48.4 years (SD 14.0), 54.8% female) of the REGISTRY study of the European Huntington's Disease Network. Lifetime suicidal ideation and suicidal behavior were assessed with the Columbia-Suicidal Severity Rating Scale. Motor symptoms and disease stage were assessed using subscales of the Unified Huntington's Disease Rating Scale, and depressed mood and irritability were assessed by the Problem Behaviors Assessment. Results Lifetime passive suicidal ideation was reported by 21.2%. Participants in stage II showed the highest prevalence rate of suicidal ideation, while participants in stage IV/V showed the highest prevalence of suicidal behavior. A lifetime suicide attempt was reported by 6.5% of the HD gene expansion carriers. In multivariate regression analyses, both suicidal ideation and suicidal behavior were associated with a depressed mood, and to a lesser extend to irritability. Limitations Results may have been affected by denial or recall bias and no conclusions can be made about the temporal and causal relationships with depressed mood and irritability because of the cross-sectional analyses. Conclusions Given the high prevalence of suicidal ideation and suicidal behavior in all stages of HD, it is important to screen HD gene expansion carriers for suicidal ideation and suicidal behavior on a regular basis in clinical practice

Survival, mortality, causes and places of death in a european huntington's disease prospective cohort

Background Huntington's disease (HD) is a rare and fatal inherited genetic disorder characterized by progressive motor, cognitive, and behavioral impairment. It leads to premature death, but data regarding advanced‐stage disease are scarce. We sought to determine HD‐associated survival, mortality, and causes and places of death. Methods Data from the European HD Network prospective study (REGISTRY) collected from 2001 through 2013 were used, including the Unified Huntington's Disease Rating Scale and death report forms. Group comparisons were performed using the t test or the χ2 test. Survival analyses were computed through Kaplan‐Meier estimates of median survival. All tests were 2‐sided with a significance level of P = 0.05. Results In total, 5164 participants were analyzed. The mean age at diagnosis was 49 years, and the mean age at death was 58 years. At the end of the study period, there were 533 deaths (10.3% of patients). Median survival was 24 years from diagnosis and 35 years from symptom onset. The most frequent causes of death were pneumonia (19.5%), other infections (6.9%), and suicide (6.6%). The most frequent places of death were the hospital (29.8%), the home (23.9%), and nursing houses (19.8%). Conclusions Patients with HD tend to die from the same conditions as patients with other neurodegenerative diseases. However, compared with nonhereditary Parkinson's disease and Alzheimer's disease, the median time from onset to death is longer, and the places of death are distinctive