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Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene. It is diagnosed following a standardized exam of motor control and often presents with cognitive decline and psychiatric symptoms. Recent studies have detected genetic loci modifying the age at onset of motor symptoms in HD, but genetic factors influencing cognitive and psychiatric presentations are unknown. We tested the hypothesis that psychiatric and cognitive symptoms in HD are influenced by the same common genetic variation as in the general population by constructing polygenic risk scores from large genome-wide association studies of psychiatric and neurodegenerative disorders, and of intelligence, and testing for correlation with the presence of psychiatric and cognitive symptoms in a large sample (n=5160) of HD patients. Polygenic risk score for major depression was associated specifically with increased risk of depression in HD, as was schizophrenia risk score with psychosis and irritability. Cognitive impairment and apathy were associated with reduced polygenic risk score for intelligence. In general, polygenic risk scores for psychiatric disorders, particularly depression and schizophrenia, are associated with increased risk of the corresponding psychiatric symptoms in HD, suggesting a common genetic liability. However, the genetic liability to cognitive impairment and apathy appears to be distinct from other psychiatric symptoms in HD. No associations were observed between HD symptoms and risk scores for other neurodegenerative disorders. These data provide a rationale for treatments effective in depression and schizophrenia to be used to treat depression and psychotic symptoms in HD.

Background Impulsive and irritable behaviour have been reported in HD from the earliest clinical descriptions of the condition, and abnormalities on various measures of impulsive behaviour have been demonstrated. However these studies had small sample sizes, and did not account for potential confounding effects in the HD population such as IQ and medication. Furthermore, the links between impulsive and irritable behaviour in HD remain unclear. Aims Determine which cognitive mechanisms contribute to irritable behaviour in HD Determine which aspects of impulsive behaviour are seen in HD Methods/Techniques We recruited HD patients and familial controls from the South Wales HD Service and performed a battery of established and novel cognitive tasks, including questionnaire measures of impulsive behavour and irritability (UPPSP, Barrett Impulsivity Scale, PBAs and Snaith), motor inhibition (stop signal task), delay discounting (Kirby instrument) and cognitive impulsivity (Iowa Gambling task). We also performed tasks of provocation (a previously reported task, and a novel task) to determine the relative contributions of impaired inhibition and excessive response to provocation in mediating irritability in HD. Results We recruited 51 HD patients and 26 controls. We found differences in response to provocation and also impaired motor inhibition on the stop signal task in the HD population, even after correcting for relevant confounders such as IQ, medication, motor impairment and psychiatric comorbidity. However, only the response to provocation was associated with irritability in HD. The tasks of delay discounting, and cognitive impulsivity did not demonstrate any differences between HD patients and controls after controlling for relevant confounders. Conclusions Irritability in HD is mediated by excessive response to provocation rather than the known impairments in motor inhibition. Other aspects of impulsivity to contribute to impulsive behaviour in HD.

Background Apathy is a core symptom of Huntington’s Disease (HD), appearing up to 10 years before the onset of motor symptoms and worsening alongside disease progression. Research into the disease needs greater focus on this symptom, but to date, limited tools exist for measuring apathy in HD. Aims This study aimed to evaluate the longitudinal validity and sensitivity of two novel computer tasks that were designed to measure apathy in HD, to assess their potential for future use in clinical trials. Method A total of 83 individuals with HD and 54 controls underwent extensive testing on a battery of existing and novel tasks that measured a range of deficits in HD. Included in this battery were the two novel tasks, the Persistence task and the Maze task, as well as the current gold-standard measures: the Problem Behaviours Assessment Scale of apathy (PBA-apathy) and the Composite Unified Huntington’s Disease Rating scale (cUHDRS). Participants were tested on the entire battery at baseline and at 12-month follow up. Results Both the Maze and Persistence tasks were able to distinguish gene positive participants from controls, but only the Maze task was found to be sensitive to change between baseline and follow up. Moreover, it appeared to be more sensitive than the cUHDRS, which did not show significant change over 12 months in this population. However, the Maze task did not show association with PBA-apathy scores, suggesting it does not measure core elements of apathy as defined by the PBA. The Persistence task was associated with PBA-apathy at baseline, but this association did not persist to follow up, suggesting that the task lacks longitudinal validity. Conclusion This study highlights the potential utility of objective computer tasks in HD research, reducing the field’s reliance on subjective self-report measures. Excitingly the findings also suggest that the Maze task could become a new objective measure of disease progression, superior to existing tools.

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

Huntington’s disease is a neurodegenerative disorder, characterised by progressive cognitive, motor and psychiatric symptoms. Patients with advanced disease presenting to emergency medical services can pose a diagnostic and management challenge for physicians unfamiliar with the condition. We describe two patients with Huntington’s disease in whom the diagnosis of traumatic spinal cord injury was delayed, discuss the role that cognitive bias and other factors played in this delay, and the lessons we can learn.

Background and purposeHuntington's disease (HD) is an autosomal dominant, neurodegenerative movement disorder, typically characterized by chorea. Dystonia is also recognized as part of the HD motor phenotype, although little work detailing its prevalence, distribution, severity and impact on functional capacity has been published to date.MethodsPatients (>18 years of age) were recruited from the Cardiff (UK) HD clinic, each undergoing a standardized videotaped clinical examination and series of functional assessment questionnaires (Unified Huntington's Disease Rating Scale, Burke-Fahn-Marsden Dystonia Rating Scale and modified version of the Toronto Western Spasmodic Torticollis Rating Scale). The presence and severity of dystonia were scored by four independent neurologists using the Burke-Fahn-Marsden Dystonia Rating Scale and Unified Huntington's Disease Rating Scale. Statistical analysis included Fisher's exact test, Wilcoxon test, anova and calculation of correlation coefficients where appropriate.ResultsForty-eight patients [91% (48/53)] demonstrated evidence of dystonia, with the highest prevalence in the left upper limb (n = 44, 83%), right upper limb most severely affected and eyes least affected. Statistically significant positive correlations (P ConclusionsWe report a high prevalence of dystonia in adult patients with HD, with worsening dystonia severity with increasing HD disease stage and motor disease duration. The recognition and management of dystonic symptoms in routine clinical practice will aid overall symptomatic treatment and functional improvement.

Background Psychiatric symptoms are common in Huntington’s disease (HD) and contribute significantly to impairment of Functional Capacity. Low mood, anxiety and irritability are common in early HD, but affective symptoms are also common in the general population and previous studies have found that the mood disorder of HD correlates poorly with motor and cognitive measures of disease progression. Apathy tends to occur later, and correlates more closely with disease progression than the mood symptoms, probably because there is no effective symptomatic treatment. Measurement of psychiatric symptoms is also confounded by anosognosia and denial, limiting the usefulness of self-report measures. Methods One of the objectives of the Repair-HD study was to validate a new Core Assessment Protocol for Intra-cerebral Transplantation in HD (CAPIT-HD2), which includes several psychiatric measures. These include a semi-structured interview, the Problem Behaviours Assessment for HD (PBA-s), and several Patient-Reported Outcome (PRO) measures including the Frontal Systems Behaviour Scale (FrSBe), the Apathy Evaluation Scale (AES), the Hospital Anxiety and Depression Scale (HADS) and two PRO irritability scales. We examined correlations between the different measures of apathy, anxiety, depression, and irritability in the baseline psychiatric data. Results All four apathy measures were significantly correlated with each other (p Conclusions The interview and self-report measures used in this study were broadly consistent in this population of patients with stage 1 and stage 2 HD, with the possible exception of depression. A future analysis of changes between the baseline and 12-month assessments will examine the potential of each of these scales to measure disease progression in HD.

Background Psychiatric symptoms are common in Huntington’s disease (HD) and contribute significantly to functional impairment. Low mood, anxiety and irritability can all occur many years before motor onset, but are also common in the general population. Apathy and perseveration (repetitive thinking or behavior) can occur before motor onset, but usually appear after diagnosis and are worst from stage 3 onwards. Previous studies have found that apathy correlates with motor and cognitive measures of disease progression, while the mood disorder does not. Methods One of the objectives of the Repair-HD study was to develop and validate a new Core Assessment Protocol for Intra-cerebral Transplantation in HD (CAPIT-HD2), which includes a psychiatric interview, the Problem Behaviours Assessment for HD (PBA-s), and several Patient-Reported Outcome (PRO) measures. The 12-month follow-up is now complete and analysis underway. We report a preliminary analysis of data from the baseline psychiatric measures. Results Cases (N=73) and controls (N=50) differed significantly for PBA-s apathy (p Conclusions This preliminary analysis confirms that apathy and perseveration correlate with disease stage, while disorders of mood (depression and anxiety) and irritability are more variable over time, and from person to person. This may reflect the complex aetiology of affective symptoms, involving psychological variables and variation in genetic susceptibility as well as HD. Symptomatic treatment with antidepressants may also mask any relationship with disease progression.

Although Huntington’s disease (HD) is rare, it deserves particular attention not only because of its devastating effects and inevitable progression as well as the familial ramifications, but also because of its potential utility as a model for other neurodegenerative diseases and psychiatric disorders. An autosomal dominant CAG trinucleotide repeat disorder, HD was first comprehensively phenotyped in an elegant study in 1872 by George Huntington, who clearly described the inheritance pattern and motor characteristics of the disease. The responsible gene locus was eventually found on chromosome 4 in a landmark paper in Cell in 1993. It is commonly accepted that 27–35 CAG repeats are ‘unstable’ and may produce disease in offspring, 36–39 repeats lead to later-onset disease and higher repeat lengths lead to inevitable disease with motor onset between the ages of 30–50 years. Several recent robust, large-scale prospective cohort studies have intensively studied the clinical and imaging biomarkers associated with disease progression in large cohorts over many years. As a result the genetics are well understood and the phenotype has been thoroughly investigated. However, the major challenge this field of research faces is in clarifying the intervening stages between genotype and phenotype, in the hope of developing disease-modifying drugs. This article reviews three papers that address significant gaps in our knowledge. Firstly, an article using a novel technique to identify biochemical pathways previously not known to be affected by mutant Huntingtin, secondly, a paper that robustly demonstrates respiratory chain enzyme dysfunction in vivo (and hence mitochondrial dysfunction in the disease), and finally, a paper that uses a large cohort to identify a putative novel phenotype associated with shorter CAG repeat lengths, challenging current assumptions about the repeat lengths necessary for disease development.

Diagnosis can prove challenging when a patient with a chronic neurological disease presents with acute deterioration. This is especially true in Huntington’s disease, where cognitive impairment is prominent. We present a case of hypercalcaemia causing an acute deterioration in physical and cognitive function in a patient with Huntington’s disease. Similarity in clinical phenotype between hypercalcaemia and Huntington’s disease, as well as failure to appreciate the acute nature of the deterioration resulted in diagnostic delay and prolonged admission. With treatment, the patient improved dramatically. The case highlights key learning points regarding assessment of patients with chronic neurological disease.

Background The course of Huntington’s disease (HD) is slowly progressive, typically over 20–30 years with little in the way of acute fluctuations, so any acute deterioration in either cognitive or motor symptoms justifies a search for an inter current illness. Here we describe three cases in which serious comorbidities were mistakenly ascribed to deterioration of HD. Case histories Case 1: A 64 year old lady with moderately advanced HD was still able to mobilise independently. Following a fall, she was admitted to hospital with increased chorea and some weakness, and a urinary tract infection was initially suspected. She went on to develop further weakness and urinary retention and eventually turned out to have a C2-7 spinal haematoma causing cord compression. She underwent decompression with some improvement. Case 2: A 58 year old man developed progressive weakness, reduced chorea and urinary retention following a fall. This was initially ascribed to progression of his HD and he was treated conservatively, but a subsequent MRI demonstrated complete dislocation of his cervical cord at C5. Surgery was not possible and he was treated palliatively. Case 3: A 42 year old woman presented with vomiting, reduced oral intake, severe constipation, confusion, restlessness and insomnia. Symptoms were attributed to her HD, but turned out to be secondary to primary hyperparathyroidism and improved with treatment. Conclusions All three cases demonstrate the diagnostic difficulties of clinical deterioration in a chronic progressive condition like HD. In all cases the initial symptoms did not trigger any suspicion of comorbidity amongst admitting physicians until further deterioration had taken place and concerns were raised by a specialist HD team. This led to delayed diagnosis which may have been associated with poor outcomes in two of the cases. Strategies for better recognising comorbidities in HD are discussed.

Background Irritability (reduced control of temper resulting in behavioural outbursts) often occurs before motor onset of Huntington’s disease (HD) and is responsible for significant impairments in quality of life and function, yet understanding of the pathophysiology is limited. Current assessments are based on diagnostic interview and self-report, but these are influenced by social context, and are unworkable in animal models. Objective tests of irritability would allow us to explore the underlying neuropsychological basis and neurobiology. Aims Established objective protocols measuring irritable, impulsive and aggressive behaviour were selected to compare with best, current assessments in order to delineate the neuropsychological basis of irritability in HD. Methods Participants carrying the gene expansion causing HD, from pre-symptomatic to moderately advanced stages were recruited. We compared scores on the Snaith Irritability scale and Problem Behaviours Assessment irritability sub-score with our battery. Subjects were tested on impulsivity measures (e.g. monetary temptation questionnaire) and provocation protocols (e.g. point subtraction aggression protocol). Results Fifty-three gene positive individuals were recruited. We recorded visual analogue scales (VAS) of irritability, anger and frustration in addition to repetitive and pre-emptive button presses (motor measures). Neither the VAS scores, motor measures or impulsivity scores correlated with standard irritability assessments. Conclusions The lack of correlation with self-report or clinician measures of irritability may reflect ineffective provocation or suggest that impulsive and irritable behaviour in HD are separate constructs, alternatively, correlation may be limited by lack of insight, drug treatment effects or impaired motor responses secondary to the motor impairments of HD.

Background Huntington’s disease (HD) is an autosomal dominant, neurodegenerative movement disorder, typically characterised by chorea. Dystonia is another frequently recognised movement disorder in HD, although little work detailing its prevalence, distribution, severity and correlation with HD characteristics has been published to date. Aims To determine the frequency and distribution of dystonia in a cohort of patients with HD. – To evaluate the severity of dystonia and its influence on the functional capacity of patients by use of standardised dystonia rating scales. Methods Patients (>18 yrs.) were consecutively recruited from the Cardiff (UK) HD-clinic, each undergoing a standardised videotaped clinical examination and functionality questionnaires (UHDRS functionality assessment and independence scale, Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) disability section and modified Toronto Western Spasmodic Torticollis Rating Scale). Dystonia severity was determined by four independent neurologists, each scoring the videotaped examinations using the BFMDRS and dystonia-section of the UHDRS. Statistical analysis included paired t-test, correlation coefficients, logistic regression analyses where appropriate. Results Eight patients have been recruited to date (5M:3F) and data collection is ongoing. We anticipate recruiting 50–60 further participants. Dystonia was deemed to be present in each body region if this was observed by the majority of the raters. Conclusions All patients recruited to date were observed to have dystonia with a varying distribution and mean severity scores. With a larger cohort we would anticipate performing further analysis to determine which, if any, clinical characteristics might be correlated with the presence and severity of dystonia. However, it is already apparent that cranio-cervical musculature is frequently involved and modification of the dystonia portion of the UHDRS might be helpful to allow for this distinction.