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MacDonald ME. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 1993;72:971–983.\ud \ud It is 28 years since the Huntington's Disease (HD) gene and mutation were identified and published in Cell by the Huntington's Disease Collaborative Research Group (HD-CRG; Fig. 1A).1 The genetic defect causing HD had been assigned to chromosome 4 in 1983 in one of the first successful linkage analyses using polymorphic DNA markers in humans,2 but it took another ten years to pinpoint the gene and determine the mutation. The long lag was largely because this research was conducted before the human genome was mapped, and was the culmination of a painstaking process involving repeatedly refining the location of the gene, based on locating markers and cloning transcripts from the genome across six independent laboratories. The nature of the genetic mutation—an expanded CAG repeat sequence—was also instrumental in the resolution of this detective story. Expanded repeats in DNA had already been associated with several diseases that had features in common with HD, such as genetic anticipation, including fragile X syndrome,3 spinal and bulbar muscular atrophy,4 and myotonic dystrophy.5-7 This meant the HD-CRG were actively looking for length mutations that segregated with disease that might indicate the presence of an expanding repeat tract. As we enter a new phase of HD research, with the advent of trials of potential disease-modifying treatments, it seems a good time to reflect on the legacy of the HD-CRG publication.

© 2021 International Parkinson and Movement Disorder Society, Background: Huntington's disease (HD) is a rare neurodegenerative disorder with protean clinical manifestations. Its management is challenging, consisting mainly of off-label treatments. Objectives: The International Parkinson and Movement Disorder Society commissioned a task force to review and evaluate the evidence of available therapies for HD gene expansion carriers. Methods: We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Eligible randomized controlled trials were identified via an electronic search of the CENTRAL, MEDLINE, and EMBASE databases. All eligible trials that evaluated one or more of 33 predetermined clinical questions were included. Risk of bias was evaluated using the Cochrane Risk of Bias tool. A framework was adapted to allow for efficacy and safety conclusions to be drawn from the balance between the GRADE level of evidence and the importance of the benefit/harm of the intervention. Results: Twenty-two eligible studies involving 17 interventions were included, providing data to address 8 clinical questions. These data supported a likely effect of deutetrabenazine on motor impairment, chorea, and dystonia and of tetrabenazine on chorea. The data did not support a disease-modifying effect for premanifest and manifest HD. There was no eligible evidence to support the use of specific treatments for depression, psychosis, irritability, apathy, or suicidality. Similarly, no evidence was eligible to support the use of physiotherapy, occupational therapy, exercise, dietary, or surgical treatments. Conclusions: Data for therapeutic interventions in HD are limited and support only the use of VMAT2 inhibitors for specific motor symptoms.

White matter (WM) alterations have been observed early in Huntington’s disease (HD) progression but their role in the disease-pathophysiology remains unknown. We exploited ultra-strong-gradient MRI to tease apart contributions of myelin (with the magnetization transfer ratio), and axon density (with the restricted volume fraction from the Composite Hindered and Restricted Model of Diffusion) to WM differences between premanifest HD patients and age- and sex-matched controls. Diffusion tensor MRI (DT-MRI) measures were also assessed. We used tractometry to investigate region-specific changes across callosal segments with well-characterized early- and late-myelinating axonal populations, while brain-wise alterations were explored with tract-based cluster analysis (TBCA). Behavioural measures were included to explore disease-associated brain-function relationships. We detected lower myelin in the rostrum of patients (tractometry: p = 0.0343; TBCA: p = 0.030), but higher myelin in their splenium (p = 0.016). Importantly, patients’ myelin and mutation size were positively associated (all p-values < 0.01), indicating that increased myelination might be a direct result of the mutation. Finally, myelin was higher than controls in younger patients but lower in older patients (p = 0.003), suggesting detrimental effects of increased myelination later in the course of the disease. Higher FR in patients’ left cortico-spinal tract (CST) (p = 0.03) was detected, and was found to be positively associated with MTR in the posterior callosum (p = 0.033), possibly suggesting compensation to myelin alterations. This comprehensive, ultra-strong gradient MRI investigation provides novel evidence of CAG-driven myelin alterations in premanifest HD which may reflect neurodevelopmental, rather than neurodegenerative disease-associated changes.

Cell replacement therapies hold the potential to restore neuronal networks compromised by neurodegenerative diseases (such as Parkinson's disease or Huntington's disease), or focal tissue damage (via a stroke or spinal cord injury). Despite some promising results achieved to date, transplanted cells typically exhibit poor survival in the central nervous system, thus limiting therapeutic efficacy of the graft. Although cell death post-transplantation is likely to be multifactorial in causality, growing evidence suggests that the lack of vascularisation at the graft site, and the resulting ischemic host environment, may play a fundamental role in the fate of grafted cells. Herein, we summarise data showing how the deprivation of either oxygen, glucose, or both in combination, impacts the survival of neurons and review strategies which may improve graft survival in the central nervous system.

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.

Aims Across the UK Huntington’s Disease (HD) services have organically grown across different healthcare specialties:- psychiatry, neurology, and genetics. Currently, there is not a UK-wide picture of how HD services are delivered, funded, or staffed at a local level or how many patients are treated in each service. The aim of this project is to undertake a survey of UK HD services to map the current organisation, resources, funding and explores the future resource needs. It is intended to capture and quantify any differences in the services across the four UK nations and in individual services. Methods/Techniques This project is being delivered through a partnership between the United Kingdom Huntington’s Disease Network (UKHDN), the Huntington’s Disease Association (HDA), the Scottish Huntington’s Association (SHA) and Roche. The project is being funded solely by Roche Products Ltd. The data will be gathered through both a quantitative questionnaire and a one-hour qualitative interview led by HDA or SHA, as appropriate. All UK HD centres will be invited to take part in this project. A report will be produced and the data will be shared with the HD Community. Results/Outcome The project team is committed to producing a report which will be publically available. This will enable the whole UK HD community to access the data collected at both a national and local level. The wider HD community will benefit from the data gathered as it has not been captured before. Conclusions It is hoped that this new data will provide a local and national picture of current services and act as evidence to support dialogues with payers/decision-makers to help secure resourcing for current and future HD service needs.

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 Evidence of best practice for long term physical activity Huntington’s disease (HD) is lacking, due in part, to inherent challenges in the delivery and evaluation of such life-style interventions. Aim To investigate the feasibility of a nested randomized controlled trial (RCT) of physical activity into Enroll-HD, an established HD cohort study. Methods We conducted a ‘Trial within a Cohort’ (TWiC) evaluation of an exercise intervention compared to usual activity in individuals with early-mid stage HD. All participants completed their usual Enroll-HD assessments and PACE-HD assessments, which included measures of fitness (predicted maximal oxygen uptake) and self-reported and quantitative measures of physical activity. We explored the use of propensity score weighting to compare the individuals in the intervention arm of the RCT to those in the cohort. Results Of the 274 participants screened, 204 met the inclusion criteria and of those, 54 (26.5%) declined to participate and 34 (16.7%) were not contactable. Recruitment targets were only narrowly missed; 59/60 (98.3%) for the cohort and 57/60 (93.5%) for the RCT. Retention rates at 12 months were ~ 85 in both groups. Percentage (%) data completeness for outcomes measures at baseline ranged from 42.3-100% and at 12 month follow up from 19.2–85.2 %. Imbalances in pretreatment confounders for the cohort and the RCT could not to be addressed via propensity score weighting likely due to small sample sizes. Conclusion A targeted recruitment strategy was instrumental in achieving target recruitment; retention at 12 months was excellent. Pre-specified criteria for minimum dataset data completion (both PACE-HD and linked Enroll-HD datasets) were met. The TWiC design, with linkage to Enroll-HD, is feasible for long-term physical activity evaluation in HD provided sample size requirements can be achieved. *PACE-HD & Enroll-HD site principal investigators Teresa Montojo. Neurology Department, Fundacion Jimenez Diaz, Madrid, Spain. Jesus Miguel Ruiz Idiago. Neuropsychiatry Unit, Hospital Mare de Deu de la Merce, Barcelona, Spain. Department of Psychiatry and Forensic Medicine, Universitat Autonoma de Barcelona, Spain. Julie Hershberg. University of Southern California, Division of Biokinesiology and Physical Therapy. Re+active physical therapy & wellness, Los Angeles, CA, USA. Yvette Bordelon. Department of Neurology, University of California, Los Angeles, CA, USA. Karen Marder, Columbia University Irving Medical Center, New York, NY, USA. Lori Quinn, Teachers College, Columbia University, New York, NY, USA. Ralf Reilmann. George-Huntington-Institute and Institute for Clinical Radiology, University of Munster, Munster, Germany. Kathrin Reetz. University Hospital Aachen, Germany. Bernhard Landwehrmeyer. University Hospital Ulm, Germany.

Background White matter (WM) impairments precede striatal atrophy and motor symptoms in Huntington’s disease (HD) but their aetiology remains unknown. Aims We exploited ultra-strong gradient MRI to disentangle the contribution of changes in axon microstructure versus changes in myelin to WM pathology in HD. Methods We assessed apparent myelin [with the magnetization transfer ratio (MTR)], and axon density [with the restricted volume fraction (FR) from the Composite Hindered and Restricted Model of Diffusion (CHARMED)] in premanifest HD patients and age- and sex-matched controls. Group differences in diffusion tensor MRI measures were also assessed. We investigated region-specific changes across the corpus callosum (CC) with tractometry and brain-wise WM microstructure abnormalities with tract-based cluster analysis (TBCA). Behavioural measures were included to explore disease-associated brain-function relationships. Results We detected lower apparent myelin in the posterior CC of patients (tractometry: p = 0.0343; TBCA: p = 0.030), and higher apparent myelin in the anterior CC (tractometry: p = 0.016). A positive association between apparent myelin and mutation size in patients (all p-values Conclusions We provide novel in vivo evidence for myelin-based WM alterations as an early feature of human HD. Critical pathogenic events were present in mutation carriers prior to clinical onset, emphasising the importance of understanding the mechanisms underlying early WM abnormalities for the discovery of new therapeutic approaches.

Multiple studies provide proof-of-concept for the benefits of cell replacement therapy (CRT) in Huntington’s disease (HD), however attaining a high survival rate of the cells post-transplantation has remained a significant challenge. Neuroinflammation is crucial in the onset and progression of HD. We hypothesise that inflammatory response to CRT surgery might be exacerbated due to a primed intrinsic inflammatory environment, partly explaining cell death and graft failure. This study aims to define innate immune responses to simulated transplantation surgery in two HD mouse models (HDQ175 & HDR6/1). Mice (96 in total: 24 HDQ175, 24 HDR6/1 and 48 wild-type control) were either kept as Control (no surgery, time 0), or underwent bilateral stereotactic needle insertion to the striatum simulating CRT surgery and culled at 1hr, 24hrs or 72hrs post-surgery. A 3mm3 cube of tissue surrounding and including the injury site was collected for RNA sequencing and multiplex cytokine analysis. The introduction of a needle into mouse brain produced an amplified pro-inflammatory response in both HD models, compared with background controls. Cytokines including IL-1β, IL-6, TNF-α were raised at 1hr and 24hrs post-needle insertion ‘p The amplified pro-inflammatory response to needle injury in HD brain compared to wild-type, reveals a state of enhanced basal pro-inflammatory activation. Thus the HD brain appears to be ‘primed’ to produce an enhanced immune response. The inflammatory reaction to surgical trauma post-CRT is likely to contribute to neural graft site hostility. Simultaneous modulation of these pro-inflammatory pathways during graft delivery may improve graft survival in CRT and advance the translation of direct intraparenchymal delivery of cells into clinical practice.

Background The relatively focal and specific loss of striatal medium spiny neurons in Huntington’s disease (HD) makes the disorder a suitable candidate for cell replacement therapy (CRT), a process involving the transplantation of donor cells to replace those lost due to disease. Whilst previous trials of CRT in HD have shown proof of principle, further investigation to demonstrate ongoing safety and efficacy is warranted. Aim Assess the safety and feasibility of transplanting an increased number of human fetal striatal cells into the striatum of people with HD. Methods TRIDENT (TRIal DEsigns for delivery of Novel Therapies in neurodegeneration) is an open label phase 1 trial using a Trial Within a Cohort (TWiC) design. A minimum of 18 participants will be enrolled in the study observational cohort, and up to five eligible participants will be randomly selected to undergo transplantation of 12-22 million fetal cells in a dose escalation paradigm. Independent reviewers will assess safety outcomes (lack of significant infection, bleeding or new neurological deficit) four weeks after surgery, and ongoing safety will be established before conducting each subsequent surgery. All participants will undergo detailed clinical and functional assessment at baseline, 6 and 12 months. Surgery will be performed one month after baseline, and transplant participants will undergo regular clinical follow-up for at least 12 months. Results 20 participants have been recruited to the observational cohort. The first transplant surgery is scheduled for July 2021. Conclusion The data collected in TRIDENT will; 1) enable assessment of the safety and feasibility of fetal cell transplants; 2) inform trial designs for complex intracranial interventions in a range of neurodegenerative conditions and 3) facilitate the development of stable surgical pipelines for delivery of future stem cell trials.

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

Background:\ud Juvenile-onset Huntington’s disease (JHD) is defined by onset at the age of 20 or younger and represents approximately 5% of all HD cases. Patients with JHD present with a broad range of symptoms and signs that only overlap partially with adult-onset HD. A greater awareness and understanding of the presentation of JHD would improve the diagnosis and treatment of this condition.\ud \ud Objective:\ud To undertake a systematic review of the literature relating to the clinical features at first presentation of JHD.\ud \ud Methods:\ud We searched MEDLINE and EMBASE for all studies describing presenting features of JHD patients, performed quality control, and collated and analysed the data.\ud \ud Results:\ud We screened 2917 records for eligibility, and included 79 studies (n = 285 individuals) in the analysis. All were case reports and case series, synthesising data from 25 different countries. Thirty-four different clinical features at presentation were identified. Four groups of symptoms or signs were present in more than 15% of cases: behavioural disturbance, falls/gait disturbance, cognitive impairment and parkinsonian features. Where data were available, the median age of onset was 9 years, 52% were female, the mutant HTT allele was transmitted paternally in 80% of cases, and the median CAG repeat length was 64.\ud \ud Conclusions:\ud JHD can present with a wide variety of symptoms and signs, with non-motor characteristics being observed most frequently. Greater recognition of these presentations will facilitate early diagnosis and management. Tailored rating scales to score motor, non-motor, and functional impairments specifically in JHD are required to standardise research studies, and are under development.

Early CNS transplantation studies used foetal derived cell products to provide a foundation of evidence for functional recovery in preclinical studies and early clinical trials. However, it was soon recognised that the practical limitations of foetal tissue make it unsuitable for widespread clinical use. Considerable effort has since been directed towards producing target cell phenotypes from pluripotent stem cells (PSCs) instead, and there now exist several publications detailing the differentiation and characterisation of PSC-derived products relevant for transplantation in Huntington’s disease (HD). In light of this progress, we ask if foetal tissue transplantation continues to be justified in HD research. We argue that (i) the extent to which accurately differentiated target cells can presently be produced from PSCs is still unclear, currently making them undesirable for studying wider CNS transplantation issues; (ii) foetal derived cells remain a valuable tool in preclinical research for advancing our understanding of which products produce functional striatal grafts and as a reference to further improve PSC-derived products; and (iii) until PSC-derived products are ready for human trials, it is important to continue using foetal cells to gather clinical evidence that transplantation is a viable option in HD and to use this opportunity to optimise practical parameters (such as trial design, clinical practices, and delivery strategies) to pave the way for future PSC-derived products.

BackgroundHuntington’s disease is caused by an expanded CAG tract in HTT. The length of the CAG tract accounts for over half the variance in age at onset of disease, and is influenced by other genetic factors, mostly implicating the DNA maintenance machinery. We examined a single nucleotide variant, rs79727797, on chromosome 5 in the TCERG1 gene, previously reported to be associated with Huntington’s disease and a quasi-tandem repeat (QTR) hexamer in exon 4 of TCERG1 with a central pure repeat.MethodsWe developed a novel method for calling perfect and imperfect repeats from exome sequencing data, and tested association between the QTR in TCERG1 and residual age at motor onset (after correcting for the effects of CAG length in the HTT gene) in 610 individuals with Huntington’s disease via regression analysis.ResultsWe found a significant association between age at onset and the sum of the repeat lengths from both alleles of the QTR (p = 2.1×10−9), with each added repeat hexamer reducing age at onset by one year (95% confidence interval [0.7, 1.4]). This association explained that previously observed with rs79727797.ConclusionsThe association with age at onset in the genome-wide association study is due to a QTR hexamer in TCERG1, translated to a glutamine/alanine tract in the protein. We could not distinguish whether this was due to cis-effects of the hexamer repeat on gene expression or of the encoded glutamine/alanine tract in the protein. These results motivate further study of the mechanisms by which TCERG1 modifies onset of HD.

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.

SummaryThe age at onset of motor symptoms in Huntington’s disease (HD) is driven by HTT CAG repeat length but modified by other genes. We used exome sequencing of 683 HD patients with extremes of onset or phenotype relative to CAG length to identify rare variants associated with clinical effect. We identified damaging coding variants in candidate modifier genes from prior genome-wide association studies associated with altered HD onset or severity. Variants in FAN1 clustered in its DNA-binding and nuclease domains and were associated predominantly with earlier onset HD. Nuclease activities of these variants correlated with residual age at motor onset of HD. Mutating endogenous FAN1 to a nuclease-inactive form in an induced pluripotent stem cell model of HD led to rates of CAG expansion comparable to those observed with complete FAN1 knock out. Together, these data implicate FAN1 nuclease activity in slowing somatic repeat expansion and hence onset of HD.

Glycosaminoglycan-based hydrogels hold great potential for applications in tissue engineering and regenerative medicine. By mimicking the natural extracellular matrix processes of growth factor binding and release, such hydrogels can be used as a sustained delivery device for growth factors. Since neural networks commonly follow well-defined, high-aspect-ratio paths through the central and peripheral nervous system, we sought to create a fiber-like, elongated growth factor delivery system. Cryogels, with networks formed at subzero temperatures, are well-suited for the creation of high-aspect-ratio biomaterials, because they have a macroporous structure making them mechanically robust (for ease of handling) yet soft and highly compressible (for interfacing with brain tissue). Unlike hydrogels, cryogels can be synthesized in advance of their use, stored with ease, and rehydrated quickly to their original shape. Herein, we use solvent-assisted microcontact molding to form sacrificial templates, in which we produced highly porous cryogel microscale scaffolds with a well-defined elongated shape via the photopolymerization of poly(ethylene glycol) diacrylate and maleimide-functionalized heparin. Dissolution of the template yielded cryogels that could load nerve growth factor (NGF) and release it over a period of 2 weeks, causing neurite outgrowth in PC12 cell cultures. This microscale template-assisted synthesis technique allows tight control over the cryogel scaffold dimensions for high reproducibility and ease of injection through fine gauge needles.

Huntington's disease (HD), a genetically determined neurodegenerative disease, is positively correlated with eye movement abnormalities in decision making. The antisaccade conflict paradigm has been widely used to study response inhibition in eye movements, and reliable performance deficits in HD subjects have been observed, including a greater number and timing of direction errors. We recorded the error rates and response latencies of early HD patients and healthy age-matched controls performing the mirror antisaccade task. HD participants displayed slower and more variable antisaccade latencies and increased error rates relative to healthy controls. A competitive accumulator-to-threshold neural model was then employed to quantitatively simulate the controls' and patients' reaction latencies and error rates and uncover the mechanisms giving rise to the observed HD antisaccade deficits. Our simulations showed that (1) a more gradual and noisy rate of accumulation of evidence by HD patients is responsible for the observed prolonged and more variable antisaccade latencies in early HD; (2) the confidence level of early HD patients making a decision is unaffected by the disease; and (3) the antisaccade performance of healthy controls and early HD patients is the end product of a neural lateral competition (inhibition) between a correct and an erroneous decision process, and not the end product of a third top-down stop signal suppressing the erroneous decision process as many have speculated.

White matter (WM) alterations have been identified as a relevant pathological feature of Huntington’s disease (HD). Increasing evidence suggests that WM changes in this disorder are due to alterations in myelin-associated biological processes. Multi-compartmental analysis of the complex gradient-echo MRI signal evolution in WM has been shown to quantify myelin in vivo, therefore pointing to the potential of this technique for the study of WM myelin changes in health and disease. This study first characterized the reproducibility of metrics derived from the complex multi-echo gradient-recalled echo (mGRE) signal across the corpus callosum in healthy participants, finding highest reproducibility in the posterior callosal segment. Subsequently, the same analysis pipeline was applied in this callosal region in a sample of premanifest HD patients (n = 19) and age, sex and education matched healthy controls (n = 21). In particular, we focused on two myelin-associated derivatives: i. the myelin water signal fraction (fm), a parameter dependent on myelin content; and ii. the difference in frequency between myelin and intra-axonal water pools (Δω), a parameter dependent on the ratio between the inner and the outer axonal radii. fm was found to be lower in HD patients (β = −0.13, p = 0.03), while Δω did not show a group effect. Performance in tests of working memory, executive function, social cognition and movement was also assessed, and a greater age-related decline in executive function was detected in HD patients (β = −0.06, p = 0.006), replicating previous evidence of executive dysfunction in HD. Finally, the correlation between fm, executive function, and proximity to disease onset was explored in patients, and a positive correlation between executive function and fm was detected (r = 0.542; p = 0.02). This study emphasises the potential of complex mGRE signal analysis for aiding understanding of HD pathogenesis and progression. Moreover, expanding on evidence from pathology and animal studies, it provides novel in vivo evidence supporting myelin breakdown as an early feature of HD.

Background\ud Cell replacement therapy (CRT) for Huntington disease (HD) requires a source of striatal (STR) progenitors capable of restoring the function lost due to STR degeneration. Authentic STR progenitors can be collected from the fetal putative striatum, or whole ganglionic eminence (WGE), but these tissues remain impractical for widespread clinical application, and alternative donor sources are required. Here we begin exploring the possibility that induced pluripotent stem cells (iPSC) derived from WGE may retain an epigenetic memory of their tissue of origin, which could enhance their ability to differentiate into STR cells.\ud Results\ud We generate four iPSC lines from human WGE (hWGE) and establish that they have a capacity similar to human embryonic stem cells with regard to their ability to differentiate toward an STR phenotype, as measured by expression and demethylation of key STR genes, while maintaining an overall different methylome. Finally, we demonstrate that these STR-differentiated hWGE iPSCs share characteristics with hWGE (i.e., authentic STR tissues) both in vitro and following transplantation into an HD model. Overall, iPSCs derived from human WGE show promise as a donor source for CRT for HD.

Background The Clinch Token Transfer Test (C3t) is a bi-manual coin transfer task that incorporates cognitive tasks to add complexity. This study explored the concurrent and convergent validity of the C3t as a simple, objective assessment of impairment that is reflective of disease severity in Huntington’s, that is not reliant on clinical expertise for administration. Methods One-hundred-and-five participants presenting with pre-manifest (n = 16) or manifest (TFC-Stage-1 n = 39; TFC-Stage-2 n = 43; TFC-Stage-3 n = 7) Huntington’s disease completed the Unified Huntington’s Disease Rating Scale and the C3t at baseline. Of these, thirty-three were followed up after 12 months. Regression was used to estimate baseline individual and composite clinical scores (including cognitive, motor, and functional ability) using baseline C3t scores. Correlations between C3t and clinical scores were assessed using Spearman’s R and visually inspected in relation to disease severity using scatterplots. Effect size over 12 months provided an indication of longitudinal behaviour of the C3t in relation to clinical measures. Results Baseline C3t scores predicted baseline clinical scores to within 9–13% accuracy, being associated with individual and composite clinical scores. Changes in C3t scores over 12 months were small ($$\Omega$$ Ω ≤ 0.15) and mirrored the change in clinical scores. Conclusion The C3t demonstrates promise as a simple, easy to administer, objective outcome measure capable of predicting impairment that is reflective of Huntington’s disease severity and offers a viable solution to support remote clinical monitoring. It may also offer utility as a screening tool for recruitment to clinical trials given preliminary indications of association with the prognostic index normed for Huntington’s disease.

Highlights • Gradient-echo data were acquired from premanifest HD patients in the callosum at 7 T. • Reproducibility of multi-compartment analysis across callosal areas was assessed. • Reduced myelin water signal fraction (fm) in HD patients suggested myelin breakdown. • Executive function correlated with callosal fm values in HD patients. • The reported approach may aid understanding of HD pathogenesis and progression., White matter (WM) alterations have been identified as a relevant pathological feature of Huntington’s disease (HD). Increasing evidence suggests that WM changes in this disorder are due to alterations in myelin‐associated biological processes. Multi-compartmental analysis of the complex gradient-echo MRI signal evolution in WM has been shown to quantify myelin in vivo, therefore pointing to the potential of this technique for the study of WM myelin changes in health and disease. This study first characterized the reproducibility of metrics derived from the complex multi-echo gradient-recalled echo (mGRE) signal across the corpus callosum in healthy participants, finding highest reproducibility in the posterior callosal segment. Subsequently, the same analysis pipeline was applied in this callosal region in a sample of premanifest HD patients (n = 19) and age, sex and education matched healthy controls (n = 21). In particular, we focused on two myelin-associated derivatives: i. the myelin water signal fraction (fm), a parameter dependent on myelin content; and ii. The difference in frequency between myelin and intra-axonal water pools (Δω), a parameter dependent on the ratio between the inner and the outer axonal radii. fm was found to be lower in HD patients (β = −0.13, p = 0.03), while Δω did not show a group effect. Performance in tests of working memory, executive function, social cognition and movement was also assessed, and a greater age-related decline in executive function was detected in HD patients (β = −0.06, p = 0.006), replicating previous evidence of executive dysfunction in HD. Finally, the correlation between fm, executive function, and proximity to disease onset was explored in patients, and a positive correlation between executive function and fm was detected (r = 0.542; p = 0.02). This study emphasises the potential of complex mGRE signal analysis for aiding understanding of HD pathogenesis and progression. Moreover, expanding on evidence from pathology and animal studies, it provides novel in vivo evidence supporting myelin breakdown as an early feature of HD.

Background Huntington’s disease (HD) is a neurodegenerative disorder leading to debilitating cognitive and motor symptoms. Impaired myelination may contribute to HD pathogenesis. We assessed baseline differences in apparent white matter (WM) myelination between HD patients and controls, and tested whether drumming training stimulates myelin remodelling in HD. We also examined whether microstructural changes were related to changes in motor and cognitive function. Methods Participants undertook two months of drumming exercises. Different aspects of working memory and executive function were assessed before and after the training. For comparability with previous studies, we assessed training-related changes in diffusion tensor magnetic resonance imaging (DT-MRI)-based metrics of fractional anisotropy (FA) and radial diffusivity (RD). Moving beyond DT-MRI, we also tested changes in the restricted diffusion signal fraction (Fr) from the composite hindered and restricted model of diffusion (CHARMED) and in the macromolecular proton fraction (MPF) from quantitative magnetization transfer (qMT). We predicted the biggest training effects in MPF, because of its greater sensitivity to myelin, compared to diffusion measures. Changes were studied in WM pathways linking the putamen and the supplementary motor area (SMA-Putamen), and within three segments of the corpus callosum (CCI, CCII, CCIII). Tracts were reconstructed using deterministic tractography. Baseline MPF differences between patients and controls were also assessed with tract-based spatial statistics (TBSS), to inspect HD-associated changes in apparent myelination. Results A reduction in baseline MPF was present in the mid section of the CC in HD group compared to controls. No significant training-associated changes were detected in FA, RD or Fr. However, after the drumming intervention, we detected increases in MPF in HD patients relative to healthy controls in the CCII, CCIII, and the right SMA-putamen. Furthermore patients improved their drumming and their executive function performance relative to controls increased after training. These behavioural changes did not correlate with the microstructural changes, suggesting that these processes follow different time courses. Conclusions Drumming training improves motor and executive performance in HD and is associated with increases in apparent WM myelin. Tailored behavioural stimulation may lead to neural benefits in early HD that could be exploited for delaying disease progression.

Huntington's disease (HD) is a rare inherited neurodegenerative disease that manifests mostly in adulthood with progressive cognitive, behavioral, and motor dysfunction. Neuronal loss occurs predominantly in the striatum but also extends to other brain regions, notably the cortex. Most patients die around 20 years after motor onset, although there is variability in the rate of progression and some phenotypic heterogeneity. The most advanced experimental therapies currently are huntingtin-lowering strategies, some of which are in stage 3 clinical trials. However, even if these approaches are successful, it is unlikely that they will be applicable to all patients or will completely halt continued loss of neural cells in all cases. On the other hand, cellular therapies have the potential to restore atrophied tissues and may therefore provide an important complementary therapeutic avenue. Pilot studies of fetal cell grafts in the 2000s reported the most dramatic clinical improvements yet achieved for this disease, but subsequent studies have so far failed to identify methodology to reliably reproduce these results. Moving forward, a major challenge will be to generate suitable donor cells from (nonfetal) cell sources, but in parallel there are a host of procedural and trial design issues that will be important for improving reliability of transplants and so urgently need attention. Here, we consider findings that have emerged from clinical transplant studies in HD to date, in particular new findings emerging from the recent multicenter intracerebral transplant HD study, and consider how these data may be used to inform future cell therapy trials.

Background Hypertension is a modifiable cardiovascular risk factor implicated in neurodegeneration and dementia risk. In Huntington's disease, a monogenic neurodegenerative disease, autonomic and vascular abnormalities have been reported. This study's objective was to examine the relationship between hypertension and disease severity and progression in Huntington's disease. Methods Using longitudinal data from the largest worldwide observational study of Huntington's disease (n = 14,534), we assessed the relationship between hypertension, disease severity, and rate of clinical progression in Huntington's disease mutation carriers. Propensity score matching was used to statistically match normotensive and hypertensive participants for age, sex, body mass index, ethnicity, and CAG length. Results Huntington's disease patients had a lower prevalence of hypertension compared with age‐matched gene‐negative controls. Huntington's disease patients with hypertension had worse cognitive function, a higher depression score, and more marked motor progression over time compared with Huntington's disease patients without hypertension. However, hypertensive patients taking antihypertensive medication had less motor, cognitive, and functional impairment than Huntington's disease patients with untreated hypertension and a later age of clinical onset compared with untreated hypertensive patients and normotensive individuals with Huntington's disease. Conclusions We report the novel finding that hypertension and antihypertensive medication use are associated with altered disease severity, progression, and clinical onset in patients with Huntington's disease. These findings have implications for the management of hypertension in Huntington's disease and suggest that prospective studies of the symptomatic or disease‐modifying potential of antihypertensives in neurodegenerative diseases are warranted. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

BackgroundHuntington’s disease (HD) is associated with a range of cognitive deficits including problems with executive function. In the absence of a disease modifying treatment, cognitive training has been proposed as a means of slowing cognitive decline; however, the impact of cognitive training in HD patient populations remains unclear. The CogTrainHD study assessed the feasibility and acceptability of home-based computerised executive function training, for people impacted by HD.MethodsThirty HD gene carriers were recruited and randomised to either executive function training or non-intervention control groups. Participants allocated to the intervention group were asked to complete executive function training three times a week for 30 min for 12 weeks in their own homes. Semi-structured interviews were conducted with participants and friends, family or carers, to determine their views on the study.Results26 out of 30 participants completed the baseline assessments and were subsequently randomised: 13 to the control group and 13 to the intervention group. 23 of the 30 participants were retained until study completion: 10/13 in the intervention group and 13/13 in the control group. 4/10 participants fully adhered to the executive function training. All participants in the control group 13/13 completed the study as intended. Interview data suggested several key facilitators including participant determination, motivation, incorporation of the intervention into routine and support from friends and family members. Practical limitations, including lack of time, difficulty and frustration in completing the intervention, were identified as barriers to study completion.ConclusionsThe CogTrainHD feasibility study provides important evidence regarding the feasibility and acceptability of a home-based cognitive training intervention for people with HD. Variable adherence to the cognitive training implies that the intervention is not feasible to all participants in its current form. The study has highlighted important aspects in relation to both the study and intervention design that require consideration, and these include the design of games in the executive function training software, logistical considerations such as lack of time, the limited time participants had to complete the intervention and the number of study visits required. Further studies are necessary before computerised executive function training can be recommended routinely for people with HD.Trial registrationClinicalTrials.gov, Registry numberNCT02990676.

ObjectiveTo assess the prevalence, timing and functional impact of psychiatric, cognitive and motor abnormalities in Huntington’s disease (HD) gene carriers, we analysed retrospective clinical data from individuals with manifest HD.MethodsClinical features of HD patients were analysed for 6316 individuals in the European REGISTRY study from 161 sites across 17 countries. Data came from clinical history and the patient-completed Clinical Characteristics Questionnaire that assessed eight symptoms: motor, cognitive, apathy, depression, perseverative/obsessive behavior, irritability, violent/aggressive behavior, and psychosis. Multiple logistic regression was used to analyse relationships between symptoms and functional outcomes.ResultsThe initial manifestation of HD is increasingly likely to be motor, and less likely to be psychiatric, as age at presentation increases, and is independent of pathogenic CAG repeat length. The Clinical Characteristics Questionnaire captures data on non-motor symptom prevalence that correlate specifically with validated clinical measures. Psychiatric and cognitive symptoms are common in HD gene carriers, with earlier onsets associated with longer CAG repeats. 42.4% of HD patients reported at least one psychiatric or cognitive symptom before motor symptoms, with depression most common. Each non-motor symptom was associated with significantly reduced total functional capacity scores.ConclusionsPsychiatric and cognitive symptoms are common and functionally debilitating in HD gene carriers. They require recognition and targeting with clinical outcome measures and treatments. However, as it is impossible to distinguish confidently between non-motor symptoms arising from HD and primary psychiatric disorders, particularly in younger pre-manifest patients, non-motor symptoms should not be used to make a clinical diagnosis of HD.

For patients with incurable neurodegenerative disorders such as Huntington's (HD) and Parkinson's disease, cell transplantation has been explored as a potential treatment option. Here, we present the first clinicopathological study of a patient with HD in receipt of cell‐suspension striatal allografts who took part in the NEST‐UK multicenter clinical transplantation trial. Using various immunohistochemical techniques, we found a discrepancy in the survival of grafted projection neurons with respect to grafted interneurons as well as major ongoing inflammatory and immune responses to the grafted tissue with evidence of mutant huntingtin aggregates within the transplant area. Our results indicate that grafts can survive more than a decade post‐transplantation, but show compromised survival with inflammation and mutant protein being observed within the transplant site.

Quantitative assessment of movement impairment in Huntington’s disease (HD) is essential to monitoring of disease progression. This study aimed to develop and validate a novel low cost, objective automated system for the evaluation of upper limb movement impairment in HD in order to eliminate the inconsistency of the assessor and offer a more sensitive, continuous assessment scale. Patients with genetically confirmed HD and healthy controls were recruited to this observational study. Demographic data including age (years), gender and Unified Huntington’s Disease Rating Scale Total Motor Score (UHDRS-TMS) were recorded. For the purposes of this study a modified upper limb motor impairment score (mULMS) was generated from the UHDRS-TMS. All participants completed a brief, standardized clinical assessment of upper limb dexterity whilst wearing a tri-axial accelerometer on each wrist and on the sternum. The captured acceleration data were used to develop an automatic classification system for discriminating between healthy and HD participants and to automatically generate a continuous Movement Impairment Score (MIS) that reflected the degree of the movement impairment. Data from 48 healthy and 44 HD participants was used to validate the developed system, which achieved 98.78% accuracy in discriminating between healthy and HD participants. The Pearson correlation coefficient between the automatic MIS and the clinician rated mULMS was 0.77 with a p-value < 0.01. The approach presented in this study demonstrates the possibility of an automated objective, consistent and sensitive assessment of the HD movement impairment.

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.

The objective of this study was to determine whether a single session of exercise was sufficient to induce cerebral adaptations in individuals with Huntington’s disease and to explore the time dynamics of any acute cerebrovascular response. In this case–control study, we employed arterial-spin labelling MRI in 19 Huntington’s disease gene-positive participants (32–65 years, 13 males) and 19 controls (29–63 years, 10 males) matched for age, gender, body mass index and self-reported activity levels, to measure global and regional perfusion in response to 20 min of moderate-intensity cycling. Cerebral perfusion was measured at baseline and 15, 40 and 60 min after exercise cessation. Relative to baseline, we found that cerebral perfusion increased in patients with Huntington’s disease yet was unchanged in control participants in the precentral gyrus (P = 0.016), middle frontal gyrus (P = 0.046) and hippocampus (P = 0.048) 40 min after exercise cessation (+15 to +32.5% change in Huntington’s disease participants, −7.7 to 0.8% change in controls). The length of the disease‐causing trinucleotide repeat expansion in the huntingtin gene predicted the change in the precentral gyrus (P = 0.03) and the intensity of the exercise intervention predicted hippocampal perfusion change in Huntington’s disease participants (P, Nineteen participants with Huntington’s disease and 19 controls underwent MRI before and immediately after a 20-min exercise intervention. A region of interest analysis found that cerebral blood flow was selectively increased in participants with Huntington’s disease in the precentral gyrus, middle frontal gyrus and hippocampus 40 min after exercise cessation, suggesting that exercise exposes latent Huntington’s disease pathology., Graphical Abstract Graphical Abstract

Interleukin-13 (IL-13) drives cells of myeloid origin towards a more anti-inflammatory phenotype, but delivery to the brain remains problematic. Herein, we show that heparin-based cryogel microcarriers load high amounts of IL-13, releasing it slowly. Intra-striatal injection of loaded microcarriers caused local up-regulation of ARG1 in myeloid cells for pro-regenerative immunomodulation in the brain.

Huntington's disease is a genetic neurodegenerative disorder. White matter alterations have recently been identified as a relevant pathophysiological feature of Huntington's disease, but their etiology and role in disease pathogenesis and progression remain unclear. Increasing evidence suggests that white matter changes in this disorder are attributed to alterations in myelin-associated biological processes. This review first discusses evidence from neurochemical studies lending support to the demyelination hypothesis of Huntington's disease, demonstrating aberrant myelination and changes in oligodendrocytes in the Huntington's brain. Next, evidence from neuroimaging studies is reviewed, the limitations of the described methodologies are discussed, and suggested interpretations of findings from published studies are challenged. Although our understanding of Huntington's associated pathological changes in the brain will increasingly rely on neuroimaging techniques, the shortcomings of these methodologies must not be forgotten. Advances in magnetic resonance imaging techniques and tissue modeling will enable a better in vivo, longitudinal characterization of the biological properties of white matter microstructure. This in turn will facilitate identification of disease-related biomarkers and the specification of outcome measures in clinical trials. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Background Exercise is emerging as an important aspect in the management of disease-related symptoms and functional decline in people with Huntington disease (HD). Long-term evaluation of physical activity and exercise participation in HD has yet to be undertaken. Objective The objective is to investigate the feasibility of a nested randomized controlled trial (RCT) alongside a longitudinal observational study of physical activity and exercise outcomes in people with HD. Design This will be a 12-month longitudinal observational study (n = 120) with a nested evaluation of a physical activity intervention (n = 30) compared with usual activity (n = 30) using a “trial within a cohort” design. Setting The study will take place in HD specialist clinics in Germany, Spain, and the United States, with intervention delivery in community settings. Participants The participants will have early-mid–stage HD and be participating in the Enroll-HD study. Intervention This will be a 12-month physical activity behavioral change intervention, delivered by physical therapists in 18 sessions, targeting uptake of aerobic exercise and increased physical activity. Measurements All participants (n = 120) will complete Enroll-HD assessments (motor, cognitive, behavioral, and quality of life) at baseline and at 12 months. Additional Physical ACtivity and Exercise Outcomes in Huntington Disease (PACE-HD) assessments include fitness (predicted maximal oxygen uptake [V o2max]), self-reported and quantitative measures of physical activity, disease-specific symptoms, and walking endurance. RCT participants (n = 60) will complete an additional battery of quantitative motor assessments and a 6-month interim assessment. Enroll-HD data will be linked to PACE-HD physical activity and fitness data. Limitations The limitations include that the embedded RCT is open, and assessors at RCT sites are not blinded to participant allocation. Conclusion PACE-HD will enable determination of the feasibility of long-term physical activity interventions in people with HD. The novel “trial within a cohort” design and incorporation of data linkage have potential to reduce participant burden. This design could be applied to other neurological diseases and movement disorders where recruitment and retention are challenging.

Background Depressed mood is common in Huntington’s disease (HD), with rates of between 33% and 69% in mutation carriers. Depressed mood is a major predictor of suicidal ideation, and is associated with significant impairments of quality of life and function. Despite this, little is understood regarding the neurobiology and cognitive processes underlying low mood and suicidal ideation in HD. Aims This study used a battery of neuropsychological tasks, that measure cognitive processes shown to be involved in major depressive disorder in the general population, and compared task performance with gold standard measures of mood and suicidal ideation in HD. Methods 53 gene positive HD patients and 26 healthy controls completed gold standard measures of mood in HD (Problem behaviours Assessment short form {PBAs}, Hospital Anxiety and Depression Scale{HADS}, Mini International Neuropsychiatric Interview{MINI}) in addition to a task battery encompassing a novel measure of depressive cognition (estimation of one’s own performance); measures of reward and effort (progressive ratio task, rewarded reaction time task); executive function measures (verbal fluency and extra-dimensional set shifting task); and a self report questionnaire of reward value. Results Patients had higher HADS scores and lower premorbid IQ than controls, no other demographic group differences were found. Group differences were seen on the executive function measures, reward value measure and depressive cognition task. Lower executive function and lower depressive cognition scores predicted suicidal ideation, but none of the other gold standard mood measures were associated with task performance. Discussion Suicidal ideation in Huntington’s disease is associated with impaired executive function and over-estimate of performance on a task of depressive cognition. Over-estimate of performance may relate to mania, which has been linked with suicidality in bipolar disorder.

Background Aberrant myelination may contribute or even precede neurodegeneration. White matter (WM) abnormalities have been widely reported in Huntington’s disease (HD), and are detectable in the pre-manifest stage, prior to symptom onset, using diffusion-weighted (DW) MRI. However, standard DW MRI metrics (e.g. fractional anisotropy (FA)) are non-specific indices of underlying biological changes. Quantitative magnetization transfer (qMT) imaging is a more sensitive measure of myelin content in white matter, as indexed by the macromolecular proton fraction (MPF). MPF is lower in early-stage HD and is related to WM abnormalities measured with DW MRI (Bourbon-Teles et al, 2017). Aims To assess whether myelin breakdown can be detected in pre-manifest HD gene carriers using qMT and DW MRI. Methods/techniques MRI was performed on a Siemens PRISMA 3T MRI Scanner at Cardiff University Brain Research Imaging Centre (CUBRIC). Eight pre-HD participants (Disease burden score; 229–299), and eight matched controls were recruited and scanned. A 3D MT-weighted fast spoiled gradient recalled-echo (SPGR) sequence was used to obtain qMT data for estimation of myelin. DW MRI was acquired and manual tractography of the cortico-spinal tract (CST), corpus callosum (CC), anterior thalamic radiation (ATR) and SMA-putamen was performed in Explore-DTI v 4.8.3. Results/outcome We will present a group-wise comparison between MPF and FA, radial and axial diffusivity (RD and AD) across all WM tracts, in line with the methods of (Bourbon-Teles et al, 2017). Planned analysis to assess group differences in diffusion metrics will be used to infer microstructural differences in WM properties including myelin content, white matter integrity and axonal damage in pre-manifest participants. Conclusions This is the first study to apply qMT MRI to measure myelin content in a pre-manifest cohort. Reduced myelination in this cohort could help inform the development of new drug treatments that aim to tackle HD in the earliest stages. Further analysis will combine this with volumetric data, to probe the early relationship between myelination and grey matter atrophy.

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 The core assessment for intra-cerebral transplantation in HD (Quinn et al, 1996) was never validated and used as a whole in previous transplant studies. Aims The main objective of Repair-HD WP5 is to develop and validate the CAPIT-HD2 as a reference battery for surgical trial. Method Through a series of workshops and in-depth review of the relevant literature, members of the consortium selected existing tests the most sensitive to change, which were retained in the provisional protocol, and identified domains in which additional tasks were required for longitudinal assessments in small cohort of patients. The new tasks were assessed in the centers in which they were developed: Creteil for cognition, Munster for motor deficits, Manchester for psychiatry and Cardiff for functional aspects and adapted for English, French and German participants. Most of them were digitalized to replace existing tasks which are heavily questionnaire-based and subject to rater bias. The development of a specified GCP and EMA compliant eCRF allowed centralization of data entry. The proposed provisional CAPIT-HD2 consisting of the best old and new tasks was then proposed for beta-testing in France, UK and Germany. 80 HD carriers and 40 controls were enrolled with the objective of assessing the psychometric properties and sensitivity to change of the core assessment battery. Participants were assessed at baseline, month 1 and month 12. Final results from all centers are expected in October 2018. Conclusion While no firm conclusion can be drawn as of now, preliminary analyses provided promising results as the new tests have proven to be efficient in discriminating between controls and patients or between stages of the disease. Moreover, decline in cognitive functions could be detected over a period of 11 months with a population as low as 20 patients and 18 controls at Creteil. Validation from the other centers is expected.

Background and aims Across the Huntington’s Disease (HD) communities, there has been some success in delivering exercise interventions in HD over the short term. In order to move the field forward we now need studies with longer term follow-up to elucidate the potential effect of exercise and physical activity on disease progression. The efficient use of existing data and consideration of patient preferences is critical for evaluation of non-drug interventions where recruitment and retention are challenging. Methods In PACE-HD we utilise a Trial-within-a-Cohort design involving six Enroll-HD sites across Europe and USA. This design involves longitudinal evaluation of physical fitness and activity in a cohort of people with manifest HD (n=120) and a nested randomized trial (RCT) at 3 sites (n=60) of 12-months exercise compared to usual care. The intervention incorporates a physical activity coaching program with goal setting, an associated workbook, and provision of exercise equipment and FitBit devices for self-monitoring of exercise. Assessments include fitness testing and the use of wearable technologies to capture and quantify dose (frequency, duration, intensity) of physical activity in a large HD cohort. Participants in the RCT allocated to usual activity and those from the observational cohort will provide reference data (n=90) from their annual Enroll-HD assessments that we will utilise to evaluate exercise effects in those randomized to supported exercise (n=30). Outcomes Should the design prove to be feasible, it will pave the way for robust evaluation of exercise in HD supported by the existing Enroll cohort.

Kv7 channels determine the resting membrane potential of neurons and regulate their excitability. Even though dysfunction of Kv7 channels has been linked to several debilitating childhood neuronal disorders, the ontogeny of the constituent genes, which encode Kv7 channels (KNCQ), and expression of their subunits have been largely unexplored. Here, we show that developmentally regulated expression of specific KCNQ mRNA and Kv7 channel subunits in mouse and human striatum is crucial to the functional maturation of mouse striatal neurons and human-induced pluripotent stem cell-derived neurons. This demonstrates their pivotal role in normal development and maturation, the knowledge of which can now be harnessed to synchronise and accelerate neuronal differentiation of stem cell-derived neurons, enhancing their utility for disease modelling and drug discovery.

Background The Q-Motor assessment battery has been designed to quantitatively measure motor deficits and progression for use in clinical studies. The assessments have shown to be able to detect subtle motor changes reliably and with absence of rater induced bias. The Q-Cog assessment battery adds assessments with an increased cognitive share, with the goal to achieve a comparable level of sensitivity for cognitive deficits of participants. The EUFP 7 funded Repair-HD (www.repair-hd.eu) study is the first to implement the Q-Cog assessments for exploratory analyses. Aims To identify sensitive and robust measures to quantitatively track cognitive progression in HD. Methods The analyzed data set includes 128 participants (52 controls, 76 HD manifest TFC stage I or II, mean age: 51 (22–78), female: 54). Statistical analyses were performed using generalized linear mixed models in R. Motor and cognitive tests were included in the assessment battery. Cognitive Assessments: Force Matching: To match a visually presented force by applying pressure on a force transducer. Blinded Force Matching: Reproduction of presented force by memory (without visual feedback). Morse Code Mimicry: To tap an acoustically presented Morse code (series of short and long beeps) on a force transducer. Trail Making: Connect dots numbered from 1 to 25 (test A) or alternating digits and letters 1,A,2,B … to 13 (test B), using a 6-axis motion tracker pen. Motor Assessments: Speeded Finger Tapping, Metronome Tapping, Grasping & Lifting, Spiral Drawing. Results Highly significant differences between control and manifest group could be found for various variables in all performed tests. Assessment of of cognitive function using the tests described is feasible and test-retest assessment shows low variability. Conclusion While results from motor tasks reproduce previous findings, the cognitive assessments, too, are able to discriminate control groups from manifest population robustly. The long-term longitudinal performance, robustness and possible redundancy of the novel variables is yet to be explored. Further analysis is required to separate motor and cognitive effects through ratios of variables of the different assessments.