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Background In this study, we asked whether differences in striatal activity during a reinforcement learning (RL) task with gain and loss domains could be one of the earliest functional imaging features associated with carrying the Huntington's disease (HD) gene. Based on previous work, we hypothesized that HD gene carriers would show either neural or behavioral asymmetry between gain and loss learning. Methods We recruited 35 HD gene carriers, expected to demonstrate onset of motor symptoms in an average of 26 years, and 35 well-matched gene-negative control subjects. Participants were placed in a functional magnetic resonance imaging scanner, where they completed an RL task in which they were required to learn to choose between abstract stimuli with the aim of gaining rewards and avoiding losses. Task behavior was modeled using an RL model, and variables from this model were used to probe functional magnetic resonance imaging data. Results In comparison with well-matched control subjects, gene carriers more than 25 years from motor onset showed exaggerated striatal responses to gain-predicting stimuli compared with loss-predicting stimuli (p = .002) in our RL task. Using computational analysis, we also found group differences in striatal representation of stimulus value (p = .0004). We found no group differences in behavior, cognitive scores, or caudate volumes. Conclusions Behaviorally, gene carriers 9 years from predicted onset have been shown to learn better from gains than from losses. Our data suggest that a window exists in which HD-related functional neural changes are detectable long before associated behavioral change and 25 years before predicted motor onset. These represent the earliest functional imaging differences between HD gene carriers and control subjects.

Background Pathological processes in Huntington's disease (HD) begin many years prior to symptom onset. Recently we demonstrated that in a premanifest cohort approximately 24 years from predicted disease onset, despite intact function, there was evidence of subtle neurodegeneration. Here, we use novel imaging techniques to determine whether macro- and micro-structural changes can be detected across the whole-brain in the same cohort. Methods 62 premanifest HD (PreHD) and 61 controls from the HD Young Adult Study (HD-YAS) were included. Grey and white matter volume, diffusion weighted imaging (DWI) measures of white matter microstructure, multiparametric maps (MPM) estimating myelin and iron content from magnetization transfer (MT), proton density (PD), longitudinal relaxation (R1) and effective transverse relaxation (R2*), and myelin g-ratio were examined. Group differences between PreHD and controls were assessed; associations between all imaging metrics and disease burden and CSF neurofilament light (NfL) were also performed. Volumetric and MPM results were corrected at a cluster-wise value of familywise error (FWE) 0.05. Diffusion and g-ratio results were corrected via threshold-free cluster enhancement at FWE 0.05. Findings We showed significantly increased R1 and R2*, suggestive of increased iron, in the putamen, globus pallidum and external capsule of PreHD participants. There was also a significant association between lower cortical R2*, suggestive of reduced myelin or iron, and higher CSF NfL in the frontal lobe and the parieto-occipital cortices. No other results were significant at corrected levels. Interpretation Increased iron in subcortical structures and the surrounding white matter is a feature of very early PreHD. Furthermore, increases in CSF NfL were linked to microstructural changes in the posterior parietal-occipital cortex, a region previously shown to undergo some of the earliest cortical changes in HD. These findings suggest that disease related process are occurring in both subcortical and cortical regions more than 20 years from predicted disease onset.

BACKGROUND: Disease-modifying treatments are in development for Huntington's disease; crucial to their success is to identify a timepoint in a patient's life when there is a measurable biomarker of early neurodegeneration while clinical function is still intact. We aimed to identify this timepoint in a novel cohort of young adult premanifest Huntington's disease gene carriers (preHD) far from predicted clinical symptom onset. METHODS: We did the Huntington's disease Young Adult Study (HD-YAS) in the UK. We recruited young adults with preHD and controls matched for age, education, and sex to ensure each group had at least 60 participants with imaging data, accounting for scan fails. Controls either had a family history of Huntington's disease but a negative genetic test, or no known family history of Huntington's disease. All participants underwent detailed neuropsychiatric and cognitive assessments, including tests from the Cambridge Neuropsychological Test Automated Battery and a battery assessing emotion, motivation, impulsivity and social cognition (EMOTICOM). Imaging (done for all participants without contraindications) included volumetric MRI, diffusion imaging, and multiparametric mapping. Biofluid markers of neuronal health were examined using blood and CSF collection. We did a cross-sectional analysis using general least-squares linear models to assess group differences and associations with age and CAG length, relating to predicted years to clinical onset. Results were corrected for multiple comparisons using the false discovery rate (FDR), with FDR 0·16). CSF neurofilament light protein (NfL), plasma NfL, and CSF YKL-40 were elevated in this far-from-onset preHD cohort compared with controls (FDR

Background Previous research has demonstrated an association between emotion recognition and apathy in a number of neurological conditions involving fronto-striatal pathology, including Parkinson’s disease and brain injury. Aims 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 HD participants from the TRACK-HD study who had an apathy score >1 on the Problem Behaviours Assessment – short version (PBA-S), 67 HD participants who reported no apathy, and 107 controls matched for age, sex and level of education. During their baseline visit, participants completed a battery of cognitive tests that include an emotion recognition task, the Hospital Depression and Anxiety Scale (HADS), and the PBA-s. Results Compared to the non-apathetic HD group and the control group, the apathetic HD group were impaired on the recognition of happy facial expressions, after controlling for depression symptomology (HADS) and general disease progression (UHDRS total motor score). This was despite no difference between the apathetic and non-apathetic groups 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 fronto-striatal pathways may broadly explain associations between emotion recognition and apathy found across a number of patient groups, further work is needed to determine what relationships exist between the recognition of specific emotions, distinct subtypes of apathy, and underlying neuropathology.

HD-YAS will study a cohort of young adult HD Gene Expansion Carriers (HDGEC) decades before expected symptom onset to characterize the very earliest signs of disease-related brain changes and identify whether there is any identifiable early functional impairment. Currently there is no detailed characterization of such a young adult HDGEC cohort and this represents the earliest time point after predictive genetic testing in which to gain disease insights. HD-YAS will be important in determining the earliest potential time window for therapeutic intervention. HD-YAS will recruit 120 participants-60 premanifest HDGECs and 60 gene negative or family controls-and will use a cross-sectional comparison with one visit per participant to assess the earliest time-point at which neurodegeneration can be detected. Participants will undergo 3T Volumetric MRI, rsfMRI and task fMRI, NODDI, and cognitive assessments including the CANTAB and EMOTICOM batteries, and biosamples such as CSF, blood and DNA will be collected to investigate biomarkers. Participants will be 18–40 years old and at-risk individuals must have a predictive genetic test; either carry the HD gene (gene-carrier) or not carry the HD gene (control). Individuals must not show any clinical symptoms of HD, have a disease burden score of ≤240, and must be willing and able to comply with the study visit and study procedures. HD-YAS began in August 2017 and is expected to complete by February 2019. HD-YAS collaborates with Enroll-HD, UK clinical genetics services and HD charity groups to identify potentially eligible participants throughout the UK. HD-YAS is funded by Wellcome, with CSF collection funded by CHDI. HD-YAS investigators – Participant Identification Site Investigators; Dr Oliver Quarrell, Dr Nayana Lahiri, Dr Andrea Nemeth, Dr Mary Porteous, Dr Elisabeth Rosser, Dr David Craufurd, Dr Rhona MacLeod, Dr Deborah Ruddy, Dr Roger Barker, Dr Simon Holden, Dr Hugh Rickards, Dr Anne Rosser, Dr Emma Hobson, Prof Angus Clarke, Dr Katherine Lachlan, Dr Reza Kiani, Dr Timothy Harrower. Thank you to the HDA, HDYO, SHA.

Introduction Disrupted gating of motor control through striatal pathways is thought to drive the development of motor symptoms in Huntington’s disease (HD). The range of motor symptoms, from chorea to bradykinesia, is thought to be driven by disruption in different striatal pathways. Aside from motor control, striatal pathways are also thought to play a key role in the expression of motivated behaviour. On this basis we asked whether the association between apathy and specific motor symptoms is in keeping with the hypothesis that apathy in HD is another manifestation of dysfunctional striatal gating. Methods Clinical data on 2608 patients with manifest HD disease was retrieved from the ENROLL-HD database. A linear mixed model was built to assess the relationship between motor symptoms and apathy (measured using the PBA and square root transformed) controlling for cognitive impairment, depression, medication use, disease duration, CAG repeat size and age. In a separate analysis the bradykinesia item was replaced by voluntary finger tapping performance. Results Although both bradykinesia and chorea were significantly associated with apathy, their effects were in opposite directions. Bradykinesia was associated with greater apathy (β=0.14, p Conclusion This analysis suggests that the processes driving distinct motor symptoms in HD may also underlie hard-to-treat psychiatric symptoms such as apathy. A common substrate and likely target for this shared mechanism is the disruption of specific striatal pathways that gate actions, decisions and motivated behaviour.

Introduction Current prescribing guidelines for the antipsychotic amisulpride are based largely on pharmacokinetic (PK) studies in young adults, and there is a relative absence of data on older patients, who are at greatest risk of developing adverse events. Methods This study aimed to develop a population PK model for amisulpride specifically in older people, by combining data from a richly sampled phase 1, single (50 mg) dose study in healthy older people (n = 20, 65–79 years), with a clinical dataset obtained during off label, low-dose (25–75 mg daily) amisulpride prescribing in older people with Alzheimer’s disease (AD) (n = 25, 69–92 years), as part of an observational study. Results After introducing a scaling factor based on body weight, age accounted for 20 % of the inter-individual variability in drug clearance (CL), resulting in a 54 % difference in CL between those aged 65 and those aged 85 years, and higher blood concentrations in older patients. Discussion These findings argue for the consideration of age and weight-based dose stratification to optimise amisulpride prescribing in older people, particularly in those aged 85 years and above. Electronic supplementary material The online version of this article (doi:10.1007/s00213-016-4379-6) contains supplementary material, which is available to authorized users.

Lightwand-guided intubation is a semi-blind technique that takes advantage of the anterior location of the trachea in relation to the oesophagus. Fibreoptic evaluation of lightwand-guided intubation has revealed a possibility of laryngeal interference and epiglottic distortion. Jaw lift, tongue traction or a combination of both have been used to assist in lightwand-guided intubation. This study fibreoptically evaluates lightwand-guided intubation using jaw lift and combined jaw and tongue traction. Eighty four patients with normal airway undergoing general anaesthesia were studied. This randomised, double blinded, cross over study was done in two phases. First phase - after achieving adequate depth of anaesthesia, a fibrescope was advanced nasally, and lightwand-guided intubation was carried out under direct fibreoptic visualisation with the aid of either jaw lift or combined jaw and tongue traction. Second phase - Extubation followed by reintubation using the other manoeuvre. Interference with laryngeal structures during intubation and position of the epiglottis at the end of intubation were noted. Epiglottic distortion (deviated to one side/infolded into trachea) was observed in 6 patients with jaw lift and 17 patients with combined jaw and tongue traction (P=0.003). Laryngeal interference was significantly higher (P=0.012) with combined manoeuvre (30/78) than with jaw lift alone (9/81). Although lightwand-guided intubation can be performed quickly and easily, interference with laryngeal structures and distortion of the epiglottis can occur. Jaw lift manoeuvre causes less laryngeal interference than combined jaw and tongue traction applied by a single operator.