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Background Huntington9s disease (HD) is an autosomal dominant neurodegenerative disorder characterised by a triad of motor, psychiatric and cognitive deficits with the latter classically attributed to disruption of frontostriatal networks. However, emerging evidence from animal models of HD suggests that some of the early cognitive deficits may have a hippocampal basis. The objective of this study was to link previous rodent findings in this area to clinical practice. Methods In this study, 94 participants included patients with early HD, premanifest HD and age-matched controls underwent hippocampal-based cognitive assessments. These included a virtual reality version of the Morris water maze, a task involved participants having to swim through a virtual pool to find a submerged platform using a joystick, and the Cambridge Neuropsychological Test Automated Battery (CANTAB) paired associates learning task, a test also known to rely on hippocampal integrity. Results Patients with early HD showed impaired performance in both the virtual Morris water maze and the CANTAB paired associates learning. Such deficits were also correlated with estimated years to diagnosis in premanifest participants. Conclusions This study highlights the merit of using analogous tests in the laboratory and clinic and demonstrates that hippocampal impairments are an early feature of HD in patients as previously shown in rodent models of the disease. As such, they could be used not only to assist in the diagnosis of disease onset, but may also be useful as an outcome measure in future therapeutic trials.

Huntington's disease (HD) is an inherited neurodegenerative disorder that is classically defined by a triad of movement and cognitive and psychiatric abnormalities with a well-established pathology that affects the dopaminergic systems of the brain. This has classically been described in terms of an early loss of dopamine D2 receptors (D2R), although interestingly the treatments most effectively used to treat patients with HD block these same receptors. We therefore sought to examine the dopaminergic system in HD not only in terms of striatal function but also at extrastriatal sites especially the hippocampus, given that transgenic (Tg) mice also exhibit deficits in hippocampal-dependent cognitive tests and a reduction in adult hippocampal neurogenesis. We showed that there was an early reduction of D2R in both the striatum and dentate gyrus (DG) of the hippocampus in the R6/1 transgenic HD mouse ahead of any overt motor signs and before striatal neuronal loss. Despite downregulation of D2Rs in these sites, further reduction of the dopaminergic input to these sites by either medial forebrain bundle lesions or receptor blockade using sulpiride was able to improve both deficits in motor performance and adult hippocampal neurogenesis. In contrast, a reduction in dopaminergic innervation of the neurogenic niches resulted in impaired neurogenesis in healthy WT mice. This study therefore provides evidence that D2R blockade improves hippocampal and striatal deficits in HD mice although the underlying mechanism for this is unclear, and suggests that agents working within this network may have greater effects than previously thought.

Cognitive features, which begin before manifestation of the motor features, are an integral part of Huntington's disease and profoundly affect quality of life. A number of neuropsychological batteries have been used to assess this aspect of the condition, many of which are difficult to administer and time consuming, especially in advanced disease. We, therefore, investigated a simple and practical way to monitor cognition using the Addenbrooke's Cognitive Examination-Revised (ACE-R) in 126 manifest Huntington's disease patients, 28 premanifest gene carriers and 21 controls. Using this test, we demonstrated a selective decrease in phonemic, but not semantic, fluency in premanifest participants Cognitive decline in manifest Huntington's disease varied according to disease severity with extensive cognitive decline observed in early-stage Huntington's disease patients, indicating that this would be an optimal stage for interventions designed to halt cognitive decline, and lesser changes in the advanced cases. We next examined cognitive performance in patients prescribed antidopaminergic drugs as these drugs are known to decrease cognition when administered to healthy volunteers. We paradoxically found that these drugs may be beneficial, as early-stage Huntington's disease participants in receipt of them had improved attention and Mini-Mental State Examination scores. In conclusion, this is the first study to test the usefulness of the ACE-R in a Huntington's disease population and demonstrates that this is a brief, inexpensive and practical way to measure global cognitive performance in clinical practice with potential use in clinical trials.

BACKGROUND: We investigated the use of a simple novel nut and bolt task in premanifest and manifest Huntington's disease (HD) patients to detect and quantify motor impairments at all stages of the disease.METHODS: Premanifest HD (n=24), manifest HD (n=27) and control (n=32) participants were asked to screw a nut onto a bolt in one direction, using three different sized bolts with their left and right hand in turn.RESULTS: We identified some impairments at all stages of HD and in the premanifest individuals, deficits in the non-dominant hand correlated with disease burden scores.CONCLUSION: This simple, cheap motor task was able to detect motor impairments in both premanifest and manifest HD and as such might be a useful quantifiable measure of motor function for use in clinical studies. (Less)

Background Huntington’s disease (HD) is an autosomal dominant condition which leads to progressive neurodegeneration and presents with a combination of motor, cognitive, affective and metabolic problems. Diagnosis of manifest HD currently relies solely on the motor features but in recent years increasing evidence has shown that the cognitive abnormalities begin before the motor features. In the brain, the HD pathology is known to affect the dopaminergic system with an early decrease in dopamine receptor 2 expression in the striatum but also other regions including the hippocampus. Interestingly, one of the most commonly used treatments for many of the features of HD block these same dopamine receptors. Aims This study therefore aims to investigate the effect of an acute dose of a commonly used dopamine receptor blocker, sulpiride, on the cognition of HD gene carriers compared to healthy controls. Methods 15 early manifest HD patients and 15 healthy controls received one dose of 200 mg of sulpiride and placebo in identical capsules in a randomised fashion. 90 min following the administration of the drug or placebo, participants were tested on a number of cognitive tasks from the computerised Cambridge Neuropsychological Test Automated Battery (CANTAB) as well as a novel hippocampal-dependent test and a risk taking task. This study has a within-subjects double-blind placebo-controlled cross-over design to minimise confounding drug effects and to allow for increased statistical power. Outcome Previous data from a pilot study in our clinic found that a similar study in a small group of manifest HD patients showed an improvement in their cognitive performance in two hippocampal tasks after taking the sulpiride. This study is therefore aiming to extend this work to investigate the effect of this drug on cognition in patient at an earlier stage of the disease process and compare it to matched controls. The study is ongoing at the moment, but hope to have preliminary results by the end of August, ready to be presented at the conference.