BACKGROUND:Huntington's disease (HD) is a rare neurodegenerative disease that presents with progressive psychological, cognitive and motor impairment. These diverse symptoms place a high burden on the patient, families and the healthcare systems they rely on. This study aimed to describe the epidemiology and clinical burden in individuals with HD compared with controls from the general population.METHODS:This cohort study utilised data from general practitioner medical records to estimate the prevalence and incidence of HD between January 2000 and December 2018. A cohort of incident HD cases were matched 1:3 to controls from the general population, in whom common clinical diagnoses, medications and healthcare interventions were compared at the time of first recorded diagnosis and at a time close to death. Incidence rates of common diagnoses and mortality were compared with matched controls in the time following HD diagnosis.RESULTS:Prevalence of HD increased between 2000 and 2018, whilst incidence remained stable. Prevalence of psychiatric diagnoses and symptomatic treatments were higher in HD cases than controls. A higher relative risk of psychotic disorders, depression, insomnia, dementia, weight loss, pneumonia and falls was observed in HD cases. Risk of death was >4 times higher in HD, with a median survival of ~12 years from first recorded diagnosis.CONCLUSIONS:This study demonstrates the significant and progressive clinical burden in individuals with HD up to 18 years after first recorded diagnosis.

Huntington’s disease (HD) is a rare, neurodegenerative disease and its complex motor, cognitive and psychiatric symptoms exert a lifelong clinical burden on both patients and their families. To describe the clinical burden and natural history of HD. This longitudinal cohort study used data from the linked Swedish national registries to describe the occurrence of comorbidities (acute and chronic), symptomatic treatments and mortality in an incident cohort of individuals who either received the first diagnosis of HD above (adult onset HD; AoHD) or below (juvenile-onset HD; JoHD) 20 years of age, compared with a matched cohort without HD from the general population. Disease burden of all individuals alive in Sweden was described during a single calendar year (2018), including the occurrence of key symptoms, treatments and hospitalizations. The prevalence of HD in 2018 was approximately 10.2 per 100,000. Of 1492 individuals with a diagnosis of HD during 2002 and 2018, 1447 had AoHD and 45 had JoHD. Individuals with AoHD suffered a higher incidence of obsessive–compulsive disorder, acute psychotic episodes, pneumonia, constipation and fractures compared with matched controls. Individuals with JoHD had higher incidence rates of epilepsy, constipation and acute respiratory symptoms. Median time to all-cause mortality in AoHD was 12.1 years from diagnosis. Patients alive with HD in Sweden in 2018 displayed a pattern of increased clinical burden for a number of years since diagnosis. This study demonstrates the significant and progressive clinical burden in individuals with HD and presents novel insights into the natural history of JoHD.

Background Where a sufficiently powered placebo-controlled clinical study is a challenge, it may be possible to use external natural history data as a comparator arm (‘external control’) to determine treatment efficacy.1 Aim To establish feasibility of using Enroll-HD as an external control by benchmarking it to the placebo arm of the GENERATION HD1 (NCT03761849) study. Methods/Techniques GENERATION HD1 inclusion criteria were applied to construct a comparable cohort from Enroll-HD. Nearest-neighbour propensity-score matching and inverse probability weighting (IPTW-ATT) methods were implemented to balance baseline characteristics between GENERATION HD1 and Enroll-HD cohorts. Regression models computed differences in annual decline of cUHDRS, TFC, TMS, SDMT, SWRT for both GENERATION HD1 placebo and Enroll-HD cohorts after controlling for CAP, CAG, age and baseline performance. Results/Outcome Both methods balanced baseline characteristics between participants in the Enroll-HD cohort and the GENERATION HD1 placebo (standardised mean difference <0.1). Superior covariate balance was achieved by IPTW-ATT (Figure 1). One-year clinical decline was greater in the Enroll-HD cohort compared with the GENERATION HD1 placebo arm (Figure 2). Conclusions Faster clinical decline in the Enroll-HD cohort compared with the GENERATION HD1 placebo arm has implications for the feasibility of using Enroll-HD as an external comparator in drug trials, since this could erroneously inflate the observed treatment effect. Slower decline in the placebo arm may be attributed to placebo effect and selection bias. Future work should explore the consistency of findings across placebo arms in Huntington’s disease trials and consider how best to utilise external data to enrich placebo cohorts. Reference Jahanshahi M, Gregg K, Davis G, Ndu A, Miller V, Vockley J, et al. The Use of External Controls in FDA Regulatory Decision Making. Therapeutic Innovation & Regulatory Science 2021;55:1019-35.

BACKGROUND Huntington's disease (HD) is a rare, genetic, neurodegenerative disease. Obtaining population-level data on epidemiology and disease management is challenging. OBJECTIVE To investigate the epidemiology, clinical manifestations, treatment, and healthcare utilization of patients with HD in Israel. METHODS Retrospective population-based cohort study, including 20 years of routinely collected data from Maccabi Healthcare Services, an insurer and healthcare provider for one-quarter of the Israeli population. RESULTS The study cohort included 109 adult patients (aged ≥18 years) diagnosed with HD, with mean age of 49.9 years and 56%females. The most common HD-related conditions were anxiety (40%), behavioral problems (34%), sleep disorders (21%), and falls (13%). Annual incidence rates for HD ranged from 0.17 to 1.34 per 100,000 from 2000 to 2018; the 2018 crude prevalence in adults was 4.36 per 100,000. Median survival from diagnosis was approximately 12 years (95%CI: 10.4-15.3). The most frequent symptomatic treatments were antidepressants (69%), antipsychotics (63%), and tetrabenazine (63%), the only drug approved for the treatment of HD chorea in Israel during the examined period. Patterns of healthcare utilization changed as disease duration increased, reflected by increased frequency of emergency department visits and home visits. CONCLUSION This retrospective population-based study provides insights into the prevalence, incidence, clinical profile, survival, and resource utilization of patients with HD in ethnically diverse Israel. The findings in this study are generally consistent with the international literature and demonstrate the value of routinely collected healthcare data as a complementary resource in HD research.

IntroductionHuntington's disease (HD) is a rare neurodegenerative disease characterized by cognitive, behavioral and motor symptoms that progressively worsen with time. Cognitive and behavioral signs of HD are generally present in the years prior to a diagnosis; however, manifest HD is typically assessed by genetic confirmation and/or the presence of unequivocal motor symptoms. Nevertheless, there is a large variation in symptom severity and rate of progression among individuals with HD.MethodsIn this retrospective study, longitudinal natural history of disease progression was modeled in individuals with manifest HD from the global, observational Enroll-HD study (NCT01574053). Unsupervised machine learning (k-means; km3d) was used to jointly model clinical and functional disease measures simultaneously over time, based on one-dimensional clustering concordance such that individuals with manifest HD (N = 4,961) were grouped into three clusters: rapid (Cluster A; 25.3%), moderate (Cluster B; 45.5%) and slow (Cluster C; 29.2%) progressors. Features that were considered predictive of disease trajectory were then identified using a supervised machine learning method (XGBoost).ResultsThe cytosine adenine guanine-age product score (a product of age and polyglutamine repeat length) at enrollment was the top predicting feature for cluster assignment, followed by years since symptom onset, medical history of apathy, body mass index at enrollment and age at enrollment.ConclusionsThese results are useful for understanding factors that affect the global rate of decline in HD. Further work is needed to develop prognostic models of HD progression as these could help clinicians with individualized clinical care planning and disease management.

Background Given the rarity of Huntington’s disease (HD), large cohort studies are warranted to better understand the clinical burden of disease in routine clinical practice. Aims To describe the incidence of clinical events in patients with HD compared with a matched cohort from the general population, and to describe differences between adult- and juvenile-onset HD. Methods This was a nationwide cohort study linking data from the Swedish National Patient Registry, Prescription Drug Registry, and Cause of Death Registry. Patients of all ages with a first diagnosis of HD (ICD-10: G10) from 2002–2018 were included and matched 1:4 (on age and sex) to a control cohort without HD. Incidence rate ratios (IRRs) and 95% confidence intervals (CI) approximated the relative risk of clinical events occurring in patients with HD vs controls after first HD diagnosis. Incidence rates (IRs) of cases were compared in those aged Results Overall, 1,492 patients with HD were matched to 5,946 controls. Median age at first diagnosis was 56 years (range: 0–96; 50% female; median follow-up: 8 years). Most outcomes were higher in patients with HD vs controls, with the greatest difference for (IRR [95%CI]): acute psychiatric episodes (14.4 [13.6–15.2]), subdural haematoma (7.5 [7.1–7.9]), communication and speech problems (6.4 [6.1–6.8]), depression (6 [5.7–6.4]), obsessive compulsive disorder (5.7 [5.4–6.0]) and anxiety disorders (4.4 [4.2–4.7]) (table 1). IRs for all studied clinical events were higher in adult-onset (N=1,447) vs juvenile-onset HD (N=45), except for epilepsy, asthma, gastrointestinal events, meningitis, and acute respiratory symptoms. Conclusions This nationwide study demonstrates considerable disease burden in HD compared with the general population. Juvenile-onset HD have higher incidence of some clinical events when compared with adult-onset HD. Study sponsored by F. Hoffmann-La Roche Ltd.

Background Huntington’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. Methods Thirty 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. Results 26 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. Conclusions The 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 registration ClinicalTrials.gov, Registry number NCT02990676 .

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 < 0.001). In both groups, exercise increased hippocampal blood flow 60 min after exercise cessation (P = 0.039). These findings demonstrate the utility of acute exercise as a clinically sensitive experimental paradigm to modulate the cerebrovasculature. Twenty minutes of aerobic exercise induced transient cerebrovascular adaptations in the hippocampus and cortex selectively in Huntington's disease participants and likely represents latent neuropathology not evident at rest.

The longitudinal dynamics of the most promising biofluid biomarker candidates for Huntington's disease (HD)-mutant huntingtin (mHTT) and neurofilament light (NfL)-are incompletely defined. Characterizing changes in these candidates during disease progression could increase our understanding of disease pathophysiology and help the identification of effective therapies. In an 80-participant cohort over 24 months, mHTT in cerebrospinal fluid (CSF), as well as NfL in CSF and blood, had distinct longitudinal trajectories in HD mutation carriers compared with controls. Baseline analyte values predicted clinical disease status, subsequent clinical progression, and brain atrophy, better than did the rate of change in analytes. Overall, NfL was a stronger monitoring and prognostic biomarker for HD than mHTT. Nonetheless, mHTT has prognostic value and might be a valuable pharmacodynamic marker for huntingtin-lowering trials.

Cardiorespiratory fitness is thought to have beneficial effects on systemic vascular health, in part, by decreasing arterial stiffness. However, in the absence of non-invasive methods, it remains unknown whether this effect extends to the cerebrovasculature. The present study uses a novel pulsed arterial spin labelling (pASL) technique to explore the relationship between cardiorespiratory fitness and arterial compliance of the middle cerebral arteries (MCAC). Other markers of cerebrovascular health, including resting cerebral blood flow (CBF) and cerebrovascular reactivity to CO2 (CVRCO2) were also investigated. Eleven healthy males aged 21 ± 2 years with varying levels of cardiorespiratory fitness (maximal oxygen uptake ([Formula: see text]O2MAX) 38–76 ml/min/kg) underwent MRI scanning at 3 Tesla. Higher [Formula: see text]O2MAX was associated with greater MCAC (R2 = 0.64, p < 0.01) and lower resting grey matter CBF (R2 = 0.75, p < 0.01). However, [Formula: see text]O2MAX was not predictive of global grey matter BOLD-based CVR (R2 = 0.47, p = 0.17) or CBF-based CVR (R2 = 0.19, p = 0.21). The current experiment builds upon the established benefits of exercise on arterial compliance in the systemic vasculature, by showing that increased cardiorespiratory fitness is associated with greater cerebral arterial compliance in early adulthood.

Movement DisordersVolume 34, Issue 4 p. 584-585 Letters: New Observations Defining pediatric huntington disease: Time to abandon the term Juvenile Huntington Disease? Oliver W. J. Quarrell MD, Corresponding Author Oliver W. J. Quarrell MD oliver.quarrell@sch.nhs.uk orcid.org/0000-0002-3818-9051 Department of Clinical Genetics, Sheffield Children's Hospital, Sheffield, UKCorrespondence to: Dr. Oliver W. J. Quarrell, Department Clinical Genetics, Sheffield Children's Hospital, Western Bank, Sheffield S10 2TH, UK; E-mail: oliver.quarrell@sch.nhs.ukSearch for more papers by this authorMartha A. Nance MD, Martha A. Nance MD Struthers Parkinson's Center, Minneapolis, Minnesota, USASearch for more papers by this authorPeg Nopoulos MD, Peg Nopoulos MD Departments of Psychiatry, Pediatrics, & Neurology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USASearch for more papers by this authorRalf Reilmann MD, PhD, Ralf Reilmann MD, PhD orcid.org/0000-0002-5904-9517 George-Huntington-Institute & Department of Radiology, University of Muenster, Muenster, Germany Department for Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, GermanySearch for more papers by this authorMayke Oosterloo MD, Mayke Oosterloo MD Department of Neurology, Maastricht University Medical Center, Maastricht, The NetherlandsSearch for more papers by this authorSarah J. Tabrizi MD, PhD, Sarah J. Tabrizi MD, PhD Department of Neurodegenerative Disease, University College London Institute of Neurology, University College London, London, UKSearch for more papers by this authorHannah Furby PhD, Hannah Furby PhD Department of Neurodegenerative Disease, University College London Institute of Neurology, University College London, London, UKSearch for more papers by this authorCarsten Saft MD, Carsten Saft MD Department of Neurology, Huntington Centre NRW, Ruhr-University Bochum, St. Josef-Hospital, Bochum, GermanySearch for more papers by this authorRaymund A. C. Roos MD, Raymund A. C. Roos MD Department of Neurology, Leiden University Medical Center Neurology, Leiden, The NetherlandsSearch for more papers by this authorFerdinando Squitieri MD, PhD, Ferdinando Squitieri MD, PhD orcid.org/0000-0002-7397-1727 Huntington and Rare Diseases Unit, Fondazione Instituto Di Ricovero e Cura a Carattere Scientifico Casa Sollievo della Sofferenza Research Hospital, San Giovanni Rotondo, ItalySearch for more papers by this authorG. Bernhard Landwehrmeyer MD, G. Bernhard Landwehrmeyer MD Department of Neurology, University of Ulm, Ulm, GermanySearch for more papers by this authorJean-Marc Burgunder MD, Jean-Marc Burgunder MD Swiss HD Center, Neurozentrum Siloah and Department of Neurology, University of Bern, Bern, SwitzerlandSearch for more papers by this authoron behalf of the Juvenile Huntington Disease Working Group of the European Huntington Disease Network, on behalf of the Juvenile Huntington Disease Working Group of the European Huntington Disease NetworkSearch for more papers by this author Oliver W. J. Quarrell MD, Corresponding Author Oliver W. J. Quarrell MD oliver.quarrell@sch.nhs.uk orcid.org/0000-0002-3818-9051 Department of Clinical Genetics, Sheffield Children's Hospital, Sheffield, UKCorrespondence to: Dr. Oliver W. J. Quarrell, Department Clinical Genetics, Sheffield Children's Hospital, Western Bank, Sheffield S10 2TH, UK; E-mail: oliver.quarrell@sch.nhs.ukSearch for more papers by this authorMartha A. Nance MD, Martha A. Nance MD Struthers Parkinson's Center, Minneapolis, Minnesota, USASearch for more papers by this authorPeg Nopoulos MD, Peg Nopoulos MD Departments of Psychiatry, Pediatrics, & Neurology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USASearch for more papers by this authorRalf Reilmann MD, PhD, Ralf Reilmann MD, PhD orcid.org/0000-0002-5904-9517 George-Huntington-Institute & Department of Radiology, University of Muenster, Muenster, Germany Department for Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, GermanySearch for more papers by this authorMayke Oosterloo MD, Mayke Oosterloo MD Department of Neurology, Maastricht University Medical Center, Maastricht, The NetherlandsSearch for more papers by this authorSarah J. Tabrizi MD, PhD, Sarah J. Tabrizi MD, PhD Department of Neurodegenerative Disease, University College London Institute of Neurology, University College London, London, UKSearch for more papers by this authorHannah Furby PhD, Hannah Furby PhD Department of Neurodegenerative Disease, University College London Institute of Neurology, University College London, London, UKSearch for more papers by this authorCarsten Saft MD, Carsten Saft MD Department of Neurology, Huntington Centre NRW, Ruhr-University Bochum, St. Josef-Hospital, Bochum, GermanySearch for more papers by this authorRaymund A. C. Roos MD, Raymund A. C. Roos MD Department of Neurology, Leiden University Medical Center Neurology, Leiden, The NetherlandsSearch for more papers by this authorFerdinando Squitieri MD, PhD, Ferdinando Squitieri MD, PhD orcid.org/0000-0002-7397-1727 Huntington and Rare Diseases Unit, Fondazione Instituto Di Ricovero e Cura a Carattere Scientifico Casa Sollievo della Sofferenza Research Hospital, San Giovanni Rotondo, ItalySearch for more papers by this authorG. Bernhard Landwehrmeyer MD, G. Bernhard Landwehrmeyer MD Department of Neurology, University of Ulm, Ulm, GermanySearch for more papers by this authorJean-Marc Burgunder MD, Jean-Marc Burgunder MD Swiss HD Center, Neurozentrum Siloah and Department of Neurology, University of Bern, Bern, SwitzerlandSearch for more papers by this authoron behalf of the Juvenile Huntington Disease Working Group of the European Huntington Disease Network, on behalf of the Juvenile Huntington Disease Working Group of the European Huntington Disease NetworkSearch for more papers by this author First published: 20 February 2019 https://doi.org/10.1002/mds.27640Citations: 13 Relevant conflicts of interests/financial disclosures: The majority of authors have been involved with clinical trials of HD. Funding agency: The European Huntington Disease Network funded a meeting of the authors. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume34, Issue4April 2019Pages 584-585 RelatedInformation

Abstract Long-term exercise interventions have been shown to be a potent trigger for both neurogenesis and vascular plasticity. However, little is known about the underlying temporal dynamics and specifically when exercise-induced vascular adaptations first occur, which is vital for therapeutic applications. In this study, we investigated whether a single session of moderate-intensity exercise was sufficient to induce changes in the cerebral vasculature. We employed arterial spin labeling magnetic resonance imaging to measure global and regional cerebral blood flow (CBF) before and after 20 min of cycling. The blood vessels’ ability to dilate, measured by cerebrovascular reactivity (CVR) to CO2 inhalation, was measured at baseline and 25-min postexercise. Our data showed that CBF was selectively increased by 10–12% in the hippocampus 15, 40, and 60 min after exercise cessation, whereas CVR to CO2 was unchanged in all regions. The absence of a corresponding change in hippocampal CVR suggests that the immediate and transient hippocampal adaptations observed after exercise are not driven by a mechanical vascular change and more likely represents an adaptive metabolic change, providing a framework for exploring the therapeutic potential of exercise-induced plasticity (neural, vascular, or both) in clinical and aged populations.

Background Limited data suggests that an altered metabolic and cardiorespiratory exercise response may affect exercise performance in individuals with Huntington's disease (HD). There is no clear exploration of the response in individuals at different stages of the disease or in relation to genetic markers. This study aimed to examine the exercise response and recovery of HD participants, and the relationship to genetic and clinical markers. Method HD gene-positive participants (n = 31; 9 pre-manifest; 22 manifest HD) and a healthy control group (n = 29) performed an incremental exercise test until exhaustion. Performance, cardiorespiratory, metabolic and perceptual responses to exercise were determined from a maximal cycle ergometer test throughout the exercise test and during a recovery period. Results During sub-maximal exercise, metabolic (lactate levels, oxygen uptake) and cardiorespiratory markers (heart rate) were elevated in HD participants compared to controls. Lactate elevation was specific to pre-manifest HD participants. Work capacity was reduced in both pre-manifest and manifest HD participants with tests terminated with no difference in metabolic, perceptual or cardiorespiratory markers. Submaximal oxygen uptake was correlated with motor score, whilst peak measures were unrelated to genetic or clinical markers. Heart rate recovery was attenuated in pre-manifest and manifest HD participants. Conclusions Our findings confirm metabolic and cardiorespiratory deficits reduce exercise performance and affect recovery from an early stage in HD, with submaximal deficits related to phenotypic expression. Exercise capacity appears to be limited by an altered movement economy, thus clinicians should consider an altered exercise response and recovery may affect prescription in HD.

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 Preclinical and post-mortem studies reveal cerebrovascular abnormalities in the HD brain. Arterial spin labelling (ASL) MRI can be used to non-invasively measure cerebral blood flow (CBF) in the HD brain, a factor known to reflect cerebrovascular health. Lower CBF has been reported in cortical and subcortical grey matter (GM) regions in early HD patients and reductions in CBF exceed changes in GM volume (Chen et al., 2012). Reduced CBF may contribute to neuronal dysfunction and cognitive performance. Alterations in CBF need to be probed earlier in the disease course. Aims To assess early signs of cerebrovascular pathology in a pre-/early-symptomatic HD cohort, by measuring cerebral blood flow (CBF) using ASL MRI. Methods 3T MRI was performed at Cardiff University Brain Research Imaging Centre (CUBRIC). Fourteen pre-/early-HD gene carriers and 19 matched control volunteers were recruited. ASL MRI was used to quantify CBF across global grey matter (GM) and subcortical regions (caudate, putamen, thalamus and hippocampus). GM volume was measured from T1 weighted anatomical scans. Cognitive tests included the SDMT, STROOP, Trailmaking, SCOLP, Forward digit span and verbal fluency tests. Results/outcome CBF was lower in HD carriers than controls in the right thalamus and right caudate, but not across global GM (p<0.05). However, global GM and left thalamus CBF was related to disease burden score (Age x (CAG −35.5), where those later in the disease showed elevated CBF. Volume was significantly lower in HD carriers than controls in caudate, putamen and thalamus, but not the hippocampus. Regional volume did not predict CBF differences. Cognitive performance was generally lower in HD group, and bilateral caudate CBF predicted performance on SDMT and SCOLP tasks, but this effect was similar in both groups. Conclusions Apparent alterations in CBF can be detected in pre-/early-HD. CBF was related to cognition, but not to GM volume. A CBF reduction in distinct subcortical regions suggest that early abnormalities are not global, and may first occur locally in key regions in HD. A disease related increase in CBF may reflect an early compensatory elevation in CBF. How CBF is related to HD pathology remains to be elucidated. Findings highlight the additional value of ASL MRI as a non-invasive measure of HD pathology that complements typical anatomical MRI approaches.