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Background Earlier disease onset in subsequent generations, called anticipation, has been observed in HD families and is attributed to an increased CAG-repeat length in the HTT gene. CAG-repeat length mutations are referred to as ‘repeat instability’ and genome-wide association studies suggest that genomic variants function as genetic modifiers of disease onset, for example by affecting DNA repair mechanisms. Aims Origin-HD aims to investigate CAG repeat instability in germline and somatic cells and evaluate for correlations with putative genetic modifiers. Understanding the mechanisms affecting repeat instability may yield testable targets for future interventions. Study design Starting Q2 2019, over 1,000 male HDGECs (ages 18–55) will be recruited from Enroll-HD participants over about two years, approximately balanced between premanifest and manifest disease. Allele and genotype frequency for each pre-specified variant of interest will be assessed after about 500 participants have been recruited. If the predicted detectable effect size is d>0.35 in the final sample of 1,000 participants, a recruitment-by-genotype recruitment approach can be adopted in parallel to the ongoing recruitment. The repeat instability in DNA from sperm and blood of study participants will be analyzed, and genetic modifier variants will be determined.

Background The dynamics of cerebrospinal fluid (CSF) flow have never been studied in Huntington’s disease (HD), and could have a clinically significant impact on the expected distribution of central nervous system delivered drugs such as huntingtin-lowering therapies. Phase contrast MRI (PCMRI) generates a signal contrast between flowing and stationary nuclei, enabling the characterisation of fluid dynamics in vivo. Objectives The objective of this study was to generate pilot data on CSF flow dynamics in HD using PCMRI, to inform the design of future intrathecal drug trials in HD. Methods We performed a prospective cross-sectional analysis of 10 age- and gender-matched healthy controls and 10 manifest HD gene expansion carriers. All participants underwent extensive clinical evaluation and cardiac-gated PCMRI at the level of the cerebral aqueduct, T1 and T8. CSF velocities and flow measurements were derived using a semi-automated method. The influence of age, gender, CAG repeat-length, serum osmolality, whole-brain volume, and ventricle volume on these measurements were tested using Spearman correlations or Fisher’s exact tests. Group comparisons between healthy controls and manifest carriers were achieved via two-sample Wilcoxon rank-sum tests. All tests were two-sided with a significance level of 0.05, and corrected for multiple comparisons. Results Twenty participants were recruited, and no significant age- and gender-imbalances were found. None of the studied covariables was found to have an effect on the CSF velocities and flow measurements after corrected for multiple comparisons. No apparent differences were found between study groups in regards to CSF velocities and flow measurements. Conclusions Although exploratory, our pilot results add to the view that CSF dynamics are not altered in HD. These results need external validation but offer reassurance that clinically-relevant disease-related alterations in CSF flow, that might justify dose-adjustments of intrathecal drugs, are very unlikely to exist.

Background Blood biomarkers of neuronal damage could facilitate clinical management of and therapeutic development for Huntington’s disease. We investigated whether neurofilament light protein (NfL) in blood is a potential prognostic marker of neurodegeneration in patients with Huntington’s disease. Methods In the 3 year, 298-participant TRACK-HD cohort, we did a retrospective analysis of the relationship between plasma NfL and clinical and neuroimaging measures previously identified as being the strongest predictors of HD progression. Cross-sectional and longitudinal relationships were analysed using random effect models of within-subject correlation. In a separate 37-participant cohort we quantified NfL in cerebrospinal fluid (CSF) and plasma. Findings Mean concentrations of plasma NfL at baseline were significantly higher in HTT mutation carriers than in controls and the difference increased with disease stage. At any given timepoint, plasma NfL correlated with clinical and MRI findings. In longitudinal analyses, baseline plasma NfL correlated significantly with subsequent decline in cognition (SDMT r=–0.374, p Interpretation NfL in plasma shows promise as a potential prognostic blood biomarker of disease onset and progression in Huntington’s disease.

Background Although Huntington’s disease (HD) is a genetically inherited disorder, it is not clear how non-genetic factors such as environment and behavior may contribute to progression. Aims We used a causal inference approach to run simulated pseudo-randomized trials in a large (n=2,914) longitudinal dataset, to study the effects of exposure to non-genetic factors on progression of HD: education, employment status, tobacco use, alcohol use, and use of recreational and therapeutic drugs. Methods Each factor was investigated in isolation while controlling for nineteen others factors (including baseline severity of HD), to guarantee that groups were well balanced at baseline on all potential confounders using propensity score (PS) weights. Outcomes were compared several years later using doubly robust (DR) outcome models. The primary outcome was a composite HD severity measure that included assessments of motor, cognitive and functional abilities. Results We only found significant evidence that antidepressant use was detrimental to HD progression over time, compared with similarly matched individuals who were not taking antidepressants (effect size difference=0.13; 95% confidence interval=0.05,0.21). Conclusions This study is the first to examine the impact of non-genetic factors on HD using causal inference methods. We show that previously reported significant factors – including alcohol and recreational drug use – were no longer causally linked to HD progression after PS weighting. This highlights the important role PS weighting can play in examining non-genetic factors contributing to HD progression, and the caution needed when interpreting findings from studies that do not attempt to use such methods.

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

Background Huntington’s disease (HD) is a progressive neurodegenerative disorder where there is a pressing need for sensitive biomarkers. Aims We assessed mutant huntingtin (mHTT) and neurofilament light (NfL) in parallel. Methods CSF mHTT, CSF NfL and plasma NfL were measured using immunoassays in 80 participants (20 healthy controls, 20 premanifest HD and 40 manifest HD) underwent clinical assessments, and standardized CSF and blood collections. Analysis included multiple linear regression models, Pearson’s correlations, receiver operating characteristics curves and samples sizes calculations. An event-based model was used to assess the temporal sequence of HD-related biomarker alterations. Results CSF mHTT, CSF NfL and plasma NfL were significantly higher as disease progressed and associated with all clinical measures. Both CSF and plasma NfL were associated with brain volume measures, but CSF mHTT was not. CSF mHTT, CSF NfL and plasma NfL were closely correlated, and highly stable within individuals. CSF mHTT had perfect accuracy for distinguishing between controls and HD mutation carriers, and both CSF and plasma NfL had excellent accuracy for distinguishing between premanifest and manifest HD. Sample size calculations suggest low participant numbers needed to incorporate these measures into clinical trials. The biofluid biomarkers emerged as the earliest detectable alterations in HD, followed by brain volume, motor and cognitive measures. Conclusion In this cross-sectional study we provide evidence to support mHTT and NfL as having favourable properties as biofluid biomarkers for HD. Our data suggests that these key biofluid biomarkers are some of the earliest detectable changes in HD.

Background Neurofilament light (NfL) protein in blood plasma has been proposed as a prognostic biomarker of neurodegeneration in a number of conditions, including Huntington’s disease (HD). Previous work has demonstrated elevated levels of NfL in HD gene expansion carriers when compared with controls, with NfL levels reflecting baseline motor and cognitive deficits as well as reduced global and regional brain volume. However, global measures provide limited insight into the regional distribution of NfL-associated pathology due to the HD gene mutation. Aims This study aims to establish the regional distribution of NfL-associated pathology in HD using voxel-based morphometry (VBM). Methods We examine associations between NfL measured in plasma and regionally-specific atrophy in cross-sectional (n=198) and longitudinal data (n=177) in HD gene expansion carriers from the international multisite TRACK-HD study. Using VBM we measured associations between baseline NfL levels and both baseline grey matter and white matter volume; and longitudinal change in grey matter and white matter over the subsequent three years in HD gene expansion carriers. Results After controlling for demographics, associations between increased NfL levels and reduced brain volume were seen in cortical and subcortical grey matter and within the white matter. After also controlling for known predictors of disease progression (age and CAG repeat length), associations were limited to the caudate and putamen. Longitudinally, NfL predicted subsequent occipital grey matter atrophy and widespread white matter reduction, both before and after correction for other predictors of disease progression. Conclusions These findings highlight the value of NfL as a dynamic marker of brain atrophy and, more generally, provide further evidence of the strong association between plasma NfL level, a candidate blood biomarker, and pathological neuronal change.

Background HD is an autosomal dominant neurodegenerative disease caused by CAG repeat expansion in the HTT gene resulting in polyglutamine expansion in the mutant huntingtin protein (mHTT) with a toxic gain-of-function disease mechanism. No disease-modifying treatments are currently available. In transgenic rodent models of HD, suppressing HTT production delays disease progression and reverses disease phenotype. A drug discovery effort, including extensive preclinical testing, was undertaken to design a well-tolerated ASO with high specificity to human HTT mRNA that potently suppresses HTT production. Design/methods In this first-in-human, multi-center, double-blind clinical trial (NCT02519036), 46 patients were randomized (3:1) to receive four doses of IONIS-HTTRx or placebo by monthly bolus intrathecal (IT) injection followed by a 4-month untreated period. Five ascending-dose cohorts were enrolled with independent DSMB review of safety, PK and target engagement prior to dose escalation. Results IONIS-HTTRx was well-tolerated at all doses tested. Adverse events were mostly mild and unrelated to study drug. There were no adverse trends in laboratory parameters. No patients prematurely discontinued from treatment. ASO was measurable in CSF and plasma. Significant, dose-dependent reductions in CSF mutant HTT (mHTT) were observed. Conclusions ASO technology has the potential to provide disease-modifying benefits to patients with neurodegenerative diseases. In this Phase 1/2a trial in early stage HD patients, IONIS-HTTRx delivered via IT injection was well tolerated with no study drug-related adverse safety signals during the treatment or follow-up periods. Significant dose-dependent reductions in CSF mHTT were observed, suggesting that IONIS-HTTRx is a promising therapeutic for the treatment of HD. Study Supported By: Ionis Pharmaceuticals

Background Smartphones, wearables and other consumer technology have high-quality sensors that enable the objective, remote, continuous and longitudinal measurement of disease symptoms. This approach has the potential to be used in future drug development and clinical practice. Aim In this study, we are exploring the feasibility of using smartphone and wrist-worn wearables for high-frequency monitoring of motor and non-motor Huntington’s disease (HD) symptoms. Method Patients with HD in the ongoing ISIS 443139-CS2 clinical study (planned enrollment, n=46) receive a smartphone and wrist-worn wearable during screening. Using these tools, patients are asked to complete daily ‘Active’ tests at home that have been designed to measure a range of motor and non-motor symptoms. Motor symptoms that are being tested include chorea and gait problems; non-motor symptoms that are in focus include cognitive processing speed. In addition, patients are asked to carry the devices with them as they go about their daily activities (i.e., ‘Passive Monitoring’). The sensor data is then securely transferred via WIFI in real-time to Roche, where it is processed and analyzed for adherence and clinically meaningful sensor data features. Results Preliminary data that has been uploaded during the first 8-week observational period in the study show that adherence is good: approximately 85% of subjects completed the entire ‘Active’ test suite on 3 or more days each week. Conclusion It is feasible to measure motor and non-motor function in patients with HD using smartphone-based assessments performed at home. This technology, including real-time data transfer and advanced analytics, provides an innovative way to learn more about patients’ daily symptoms in the clinical trial setting. Data collection in additional patient cohorts will be an important next step to broaden experience with this approach. Funded by Ionis Pharmaceuticals Inc and F. Hoffmann-La Roche.

Huntington's disease (HD) is a chronic progressive neurodegenerative condition where new markers of disease progression are needed. So far no disease-modifying interventions have been found, and few interventions have been proven to alleviate symptoms. This may be partially explained by the lack of reliable indicators of disease severity, progression, and phenotype.Biofluid biomarkers may bring advantages in addition to clinical measures, such as reliability, reproducibility, price, accuracy, and direct quantification of pathobiological processes at the molecular level; and in addition to empowering clinical trials, they have the potential to generate useful hypotheses for new drug development.In this chapter we review biofluid biomarker reports in HD, emphasizing those we feel are likely to be closest to clinical applicability.

Biomarkers of Huntington’s disease (HD) in cerebrospinal fluid (CSF) could be of value in elucidating the biology of this genetic neurodegenerative disease, as well as in the development of novel therapeutics. Deranged synaptic and immune function have been reported in HD, and concentrations of the synaptic protein neurogranin and the microglial protein TREM2 are increased in other neurodegenerative diseases. We therefore used ELISAs to quantify neurogranin and TREM2 in CSF samples from HD mutation carriers and controls. CSF neurogranin concentration was not significantly altered in HD compared to controls, nor was it significantly associated with disease burden score, total functional capacity or motor score. An apparent increase in CSF TREM2 in manifest HD was determined to be due to increasing TREM2 with age. After age adjustment, there was no significant alteration of TREM2 in either HD group, nor any association with motor, functional or cognitive score, or brain volume quantified by MRI. Both analyses were well-powered, and sample size calculations indicated that several thousand samples per group would be needed to prove that disease-associated alterations do in fact exist. We conclude that neither neurogranin nor TREM2 is a useful biofluid biomarker for disease processes in Huntington’s disease.

© 2018 – IOS Press and the authors. All rights reserved. This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License (CC BY-NC 4.0), In the second edition of the Huntington’s Disease Clinical Trials Corner we list all currently registered and ongoing clinical trials, summarise the top-line results of the recently-announced IONIS-HTTRX trial (NCT02519036), expand on Wave Life Sciences’ PRECISION-HD1 (NCT03225833) and PRECISION-HD2 (NCT03225846), and cover one recently finished trial: the FIRST-HD deutetrabenazine trial (NCT01795859).

Huntington's disease (HD) is a chronic progressive neurodegenerative condition where new markers of disease progression are needed. So far no disease-modifying interventions have been found, and few interventions have been proven to alleviate symptoms. This may be partially explained by the lack of reliable indicators of disease severity, progression, and phenotype.Biofluid biomarkers may bring advantages in addition to clinical measures, such as reliability, reproducibility, price, accuracy, and direct quantification of pathobiological processes at the molecular level; and in addition to empowering clinical trials, they have the potential to generate useful hypotheses for new drug development.In this chapter we review biofluid biomarker reports in HD, emphasizing those we feel are likely to be closest to clinical applicability.

ObjectiveNeurofilament light (NfL) protein in blood plasma has been proposed as a prognostic biomarker of neurodegeneration in a number of conditions, including Huntington disease (HD). This study investigates the regional distribution of NfL-associated neural pathology in HD gene expansion carriers.MethodsWe examined associations between NfL measured in plasma and regionally specific atrophy in cross-sectional (n = 198) and longitudinal (n = 177) data in HD gene expansion carriers from the international multisite TRACK-HD study. Using voxel-based morphometry, we measured associations between baseline NfL levels and both baseline gray matter and white matter volume; and longitudinal change in gray matter and white matter over the subsequent 3 years in HD gene expansion carriers.ResultsAfter controlling for demographics, associations between increased NfL levels and reduced brain volume were seen in cortical and subcortical gray matter and within the white matter. After also controlling for known predictors of disease progression (age and CAG repeat length), associations were limited to the caudate and putamen. Longitudinally, NfL predicted subsequent occipital gray matter atrophy and widespread white matter reduction, both before and after correction for other predictors of disease progression.ConclusionsThese findings highlight the value of NfL as a dynamic marker of brain atrophy and, more generally, provide further evidence of the strong association between plasma NfL level, a candidate blood biomarker, and pathologic neuronal change.

Quantification of disease-associated proteins in the cerebrospinal fluid (CSF) has been critical for the study and treatment of several neurodegenerative disorders; however, mutant huntingtin protein (mHTT), the cause of Huntington's disease (HD), is at very low levels in CSF and, to our knowledge, has never been measured previously.We developed an ultrasensitive single-molecule counting (SMC) mHTT immunoassay that was used to quantify mHTT levels in CSF samples from individuals bearing the HD mutation and from control individuals in 2 independent cohorts.This SMC mHTT immunoassay demonstrated high specificity for mHTT, high sensitivity with a femtomolar detection threshold, and a broad dynamic range. Analysis of the CSF samples showed that mHTT was undetectable in CSF from all controls but quantifiable in nearly all mutation carriers. The mHTT concentration in CSF was approximately 3-fold higher in patients with manifest HD than in premanifest mutation carriers. Moreover, mHTT levels increased as the disease progressed and were associated with 5-year onset probability. The mHTT concentration independently predicted cognitive and motor dysfunction. Furthermore, the level of mHTT was associated with the concentrations of tau and neurofilament light chain in the CSF, suggesting a neuronal origin for the detected mHTT.We have demonstrated that mHTT can be quantified in CSF from HD patients using the described SMC mHTT immunoassay. Moreover, the level of mHTT detected is associated with proximity to disease onset and diminished cognitive and motor function. The ability to quantify CSF mHTT will facilitate the study of HD, and mHTT quantification could potentially serve as a biomarker for the development and testing of experimental mHTT-lowering therapies for HD.Not applicable.CHDI Foundation Inc.; Medical Research Council (MRC) UK; National Institutes for Health Research (NIHR); Rosetrees Trust; Swedish Research Council; and Knut and Alice Wallenberg Foundation.

There is an unmet need to reliably and non-invasively monitor disease progression in preclinical Huntington’s disease (HD) models. As a marker of axonal damage, neurofilament light chain (NfL) has been suggested a marker for neurodegeneration. NfL concentrations in blood and CSF were recently shown to have prognostic value for clinical HD progression and brain atrophy. We therefore hypothesized that CSF and blood NfL concentrations could be useful preclinical HD markers, reflecting underlying pathology. To test our hypothesis we utilized the R6/2 mouse model of HD and measured NfL concentrations in CSF and serum using the ultrasensitive Single molecule array (Simoa) platform. In addition, we assessed HD mouse disease characteristics. We found robust increases of NfL in CSF and serum in R6/2 mice compared to wild-type littermates. CSF and serum concentrations of NfL were significantly correlated, suggesting similar marker potential of serum NfL. CSF and serum concentrations of NfL correlated with disease severity, as assessed by striatal volume and body weight loss. We here provide evidence that CSF and blood NfL concentrations can be used as accessible and reliable pre-clinical HD markers. This will be of potential use for monitoring HD mouse model disease progression and evaluating preclinical disease-modifying treatment response.

Background Tetrabenazine is the only US Food and Drug Administration‐approved drug for Huntington's disease, and deutetrabenazine was recently tested against placebo. A switching‐trial from tetrabenazine to deutetrabenazine is underway, but no head‐to‐head, blinded, randomized controlled trial is planned. Using meta‐analytical methodology, the authors compared these molecules. Methods RCTs comparing tetrabenazine or deutetrabenazine with placebo in Huntington's disease were searched. The authors assessed the Cochrane risk‐of‐bias tool, calculated indirect treatment comparisons, and applied the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. Results The evidence network for this report comprised 1 tetrabenazine trial and 1 deutetrabenazine trial, both against placebo. Risk of bias was moderate in both. Participants in the tetrabenazine and deutetrabenazine trials did not differ significantly on motor scores or adverse events. Depression and somnolence scales significantly favored deutetrabenazine. Conclusion There is low‐quality evidence that tetrabenazine and deutetrabenazine do not differ in efficacy or safety. It is important to note that these results are likely to remain the only head‐to‐head comparison between these 2 compounds in Huntington's disease.

Cerebrospinal fluid (CSF) is enriched in brain-derived components and represents an accessible and appealing means of interrogating the CNS milieu to study neurodegenerative diseases and identify biomarkers to facilitate the development of novel therapeutics. Many such CSF biomarkers have been proposed for Huntington's disease (HD) but none has been validated for clinical trial use. Across many studies proposing dozens of biomarker candidates, there is a notable lack of statistical power, consistency, rigor and validation. Here we review proposed CSF biomarkers including neurotransmitters, transglutaminase activity, kynurenine pathway metabolites, oxidative stress markers, inflammatory markers, neuroendocrine markers, protein markers of neuronal death, proteomic approaches and mutant huntingtin protein itself. We reflect on the need for large-scale, standardized CSF collections with detailed phenotypic data to validate and qualify much-needed CSF biomarkers for clinical trial use in HD.

Huntington's disease (HD) is a hereditary neurodegenerative condition with no therapeutic intervention known to alter disease progression, but several trials are ongoing and biomarkers of disease progression are needed. Tau is an axonal protein, often altered in neurodegeneration, and recent studies pointed out its role on HD neuropathology. Our goal was to study whether cerebrospinal fluid (CSF) tau is a biomarker of disease progression in HD. After informed consent, healthy controls, pre‐symptomatic and symptomatic gene expansion carriers were recruited from two HD clinics. All participants underwent assessment with the Unified HD Rating Scale ’99 (UHDRS). CSF was obtained according to a standardized lumbar puncture protocol. CSF tau was quantified using enzyme‐linked immunosorbent assay. Comparisons between two groups were tested using ancova. Pearson's correlation coefficients were calculated for disease progression. Significance level was defined as p

IntroductionImmune system activation is involved in Huntington's disease (HD) pathogenesis and biomarkers for this process could be relevant to study the disease and characterise the therapeutic response to specific interventions. We aimed to study inflammatory cytokines and microglial markers in the CSF of HD patients.MethodsCSF TNF-α, IL-1β, IL-6, IL-8, YKL-40, chitotriosidase, total tau and neurofilament light chain (NFL) from 23 mutation carriers and 14 healthy controls were assayed.ResultsCSF TNF-α and IL-1β were below the limit of detection. Mutation carriers had higher YKL-40 (p = 0.003), chitotriosidase (p = 0.015) and IL-6 (p = 0.041) than controls. YKL-40 significantly correlated with disease stage (p = 0.007), UHDRS total functional capacity score (r = -0.46, p = 0.016), and UHDRS total motor score (r = 0.59, p = 4.5*10-4) after adjustment for age.ConclusionYKL-40 levels in CSF may, after further study, come to have a role as biomarkers for some aspects of HD. Further investigation is needed to support our exploratory findings.

Huntington's disease (HD) is a devastating autosomal-dominant neurodegenerative condition caused by a CAG repeat expansion in the gene encoding huntingtin which is characterised by progressive motor impairment, cognitive decline and neuropsychiatric disturbances. There are currently no disease-modifying treatments available to patients, but a number of therapeutic strategies are currently being investigated, chief among them are nucleotide-based 'gene silencing' approaches, modulation of huntingtin post-translation modification and enhancing clearance of the mutant protein. In 2008, the authors' review highlighted the need to develop and validate biomarkers and provided a systematic head-to-head comparison of such measures. They searched the PubMed database for publications, which covered each of the subheadings mentioned below. They identified from these list studies which had relevance to biomarker development, as defined in their previous review. Building on a tradition of collaborative research in HD, great advances have been made in the field since that time and a range of outcome measures are now being recommended in order to assess efficacy in future therapeutic trials.

The discovery in 1993 of the genetic abnormality that causes Huntington's disease triggered an explosion in our understanding of this inherited neurodegenerative disorder (The Huntington's Disease Collaborative Research Group, 1993). Since the Huntington's disease mutation is fully penetrant, everyone with the same underlying CAG triplet repeat expansion in the huntingtin ( HTT ) gene will develop a devastating combination of motor, cognitive and psychiatric disturbances. The monogenic nature of Huntington's disease suggests that disease modifying therapies should be within reach. Currently, however, no such treatments exist (Mestre et al. , 2009). Nevertheless, much has been done to characterize the huntingtin (Htt) protein and the effects of its toxic twin, mutant huntingtin. We know that Htt is a large and ubiquitously expressed protein with a range of possible functions, and that Huntington's disease is predominantly caused by the damaging effects of mutant Htt on neurons. A range of animal models recapitulate the molecular, cellular and clinical phenotypes of Huntington's disease, enhancing our understanding and facilitating the search for treatments (Ross and Tabrizi, 2011). Numerous potential pathogenic mechanisms have been identified, leading to promising therapeutic approaches in transgenic Huntington's disease mice and other models. Although none has yet been found effective in human patients, there is optimism in the field that Huntington's disease is a disease for which the goal of effective therapy might be achieved (Munoz-Sanjuan and Bates, 2011). Two articles in this issue of Brain highlight the Huntington's disease research community's multi-faceted approach to developing new treatments for Huntington's disease. Grondin and colleagues report success in a 6-month study of HTT gene silencing using RNA interference in the adult non-human primate brain (Grondin et al. , 2012); while Labbadia et al. (2012) describe the means by which a molecular chaperone can suppress aggregation of disease-associated Htt complexes. Gene silencing is an …

Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder caused by an expanded CAG repeat in the gene encoding huntingtin (HTT). Therapeutic approaches to lower mutant HTT (mHTT) levels are expected to proceed to human trials, but noninvasive quantification of mHTT is not currently possible. The importance of the peripheral immune system in neurodegenerative disease is becoming increasingly recognized. Peripheral immune cells have been implicated in HD pathogenesis, but HTT levels in these cells have not been quantified before. A recently described time-resolved Forster resonance energy transfer (TR-FRET) immunoassay was used to quantify mutant and total HTT protein levels in leukocytes from patients with HD. Mean mHTT levels in monocytes, T cells, and B cells differed significantly between patients with HD and controls and between pre-manifest mutation carriers and those with clinical onset. Monocyte and T cell mHTT levels were significantly associated with disease burden scores and caudate atrophy rates in patients with HD. mHTT N-terminal fragments detected in HD PBMCs may explain the progressive increase in mHTT levels in these cells. These findings indicate that quantification of mHTT in peripheral immune cells by TR-FRET holds significant promise as a noninvasive disease biomarker.

Huntington's disease (HD) is caused by an expanded CAG tract in the Interesting transcript 15 (IT15) gene encoding the 350 kDa huntingtin protein. Cellular stresses can trigger the release of huntingtin from the endoplasmic reticulum, allowing huntingtin nuclear entry. Here, we show that endogenous, full-length huntingtin localizes to nuclear cofilin-actin rods during stress and is required for the proper stress response involving actin remodeling. Mutant huntingtin induces a dominant, persistent nuclear rod phenotype similar to that described in Alzheimer's disease for cytoplasmic cofilin-actin rods. Using live cell temporal studies, we show that this stress response is similarly impaired when mutant huntingtin is present, or when normal huntingtin levels are reduced. In clinical lymphocyte samples from HD patients, we have quantitatively detected cross-linked complexes of actin and cofilin with complex formation varying in correlation with disease progression. By live cell fluorescence lifetime imaging measurement-Förster resonant energy transfer studies and western blot assays, we quantitatively observed that stress-activated tissue transglutaminase 2 (TG2) is responsible for the actin-cofilin covalent cross-linking observed in HD. These data support a direct role for huntingtin in nuclear actin re-organization, and describe a new pathogenic mechanism for aberrant TG2 enzymatic hyperactivity in neurodegenerative diseases.

Acute meningococcal meningitis in adults can be complicated by cranial neuropathies and more rarely by myelopathy. A 55-year-old woman presented with acute bacterial meningitis requiring intubation and was treated with intravenous antibiotics and dexamethasone. Cerebrospinal fluid 16S PCR was positive for Neisseria meningitidis and latex agglutination confirmed the W135 serotype. Ten days after presentation she developed mild upper limb and severe lower limb weakness with hyperreflexia, despite resolution of meningism and improvement of inflammatory markers. On the next day she developed complete bilateral hearing loss and bilateral facial palsy. Magnetic resonance imaging with contrast showed bilateral enhancement of VIIth and VIIIth cranial nerves, with focal signal change within the thoracic spinal cord. Audiometry confirmed complete sensorineural deafness. She was treated with five days of intravenous methylprednisolone and continued a further nine days of intravenous antibiotics. Four weeks after onset, she remained completely deaf with mild improvement of limb and facial weakness. We report a case of acute meningococcal meningitis complicated by presumed extensive vasculitis leading to myelopathy and delayed onset of multiple cranial neuropathies. There was an unusual biphasic presentation and the vasculitis was apparently ameliorated by glucocorticoids, suggesting conventional steroid recommendations may occasionally be inadequate.

Immune dysfunction, a well-established feature of neuroinflammatory disease, is increasingly recognized in neurodegenerative conditions. Its role is emerging as an early and active participant in neuropathology. Inflammation could be modified, with disease-slowing effects, by targeted interventions; it is also readily detectable and could serve as a source of valuable biomarkers.

Tracking progression in neurodegenerative diseases is hampered by the limitations of the clinical rating scales, which are seldom linear, suffer from floor and ceiling effects, lack the ability to distinguish symptomatic change from disease modification, and are limited by imperfect intra- and inter-rater reliability. The promise of an era of neuroprotective therapies renders urgent the search for reliable measures of progression. Biomarkers have the potential to enhance several aspects of both therapeutic trials and clinical practice. MRI-based measures of cerebral volume can provide a surrogate for neuronal loss and several techniques have been applied to elucidate disease processes, aid diagnosis, and enable monitoring of progression in a variety of Parkinsonian disorders, including Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy and Huntington's disease. We review the approaches to, and findings revealed by, serial volumetric MRI in these disorders.

Objective: Caudate atrophy rate measured from serial MRI is proposed as a biomarker of HD progression that may be of use in assessing putative disease-modifying agents. Manual measurement techniques are the most widely applied but are time-consuming. We describe and evaluate an automated technique based on a local registration and boundary shift integral (BSI) approach at the caudate–CSF and caudate–white matter boundaries; caudate boundary shift integral (CBSI). Methods: Two-year caudate volume change was measured in controls, premanifest HD and early HD using the CBSI and compared with a detailed manual measure in terms of 1) raw caudate volume change, 2) group differentiation, 3) associations with clinical variables and 4) rater requirements. CBSI additivity was assessed by comparing measurements over a single scan pair (baseline → 2 years), with the sum of measurements from two scan pairs (baseline → 1 year → 2 years). Results: Techniques produced comparable caudate volume change measurements, although CBSI under-reported by 0.04 ml relative to manual. Both techniques distinguished controls, premanifest and early HD with a stepwise increase in rates across groups. Higher rates (CBSI and manual) were associated with increased proximity to estimated disease onset but not clinical change scores. CBSI reduced rater requirements by 2/3 (2 h per subject) relative to manual for this three time-point investigation. CBSI measurements over one scan pair showed good agreement with the sum of measurements from two scan pairs. Conclusions: CBSI results were comparable to a manual measure but with reduced rater requirements. CBSI may be of use in large-scale studies of HD.

No treatments have yet been shown to slow the progression of the inherited neurodegenerative disorder Huntington's disease (HD) in humans, but several attempts at disease modification in animal models have been successful. Human clinical trials based on present clinical measures would require unfeasibly large subject numbers, particularly in premanifest HD mutation carriers, and the main aim of biomarker research in HD is to enable the development of surrogate end points to enable such trials to be conducted. In this article, the imaging, biofluid, quantitative motor and cognitive measures that have been shown to reflect the progression of HD are reviewed. A conceptual framework and pipeline for evaluating the large number of potential HD biomarkers is presented, and the need for systematic head-to-head comparison of candidate markers is highlighted.

Huntington's disease (HD) is an inherited neurodegenerative disorder that classically presents with motor, cognitive and psychiatric symptoms. However, other abnormalities also occur in this condition, notably deficient recognition of facial emotional expressions. Deficits in emotion recognition impact significantly on the lives of HD patients and their families and thus it is important to clarify the onset and pattern of impairment. This study investigated facial emotion recognition in a large cohort of early HD patients, and premanifest gene-carriers. We used voxel-based morphometry (VBM) to examine the neuroanatomical correlates of emotion recognition performance. Forty patients with early HD, 21 premanifest gene carriers and 20 controls were assessed using 24 faces from the Ekman Pictures of Facial Affect, and volumetric brain MRI. The HD group was significantly worse than controls at recognising, surprise, disgust, anger and fear, and worse than the premanifest group at recognising disgust and anger. When patient data were expressed as z-scores, recognition of anger was significantly worse than disgust in the early HD group. In the VBM analysis, these deficits were associated with common regional atrophy: impaired recognition of surprise, disgust, anger and fear were all associated with striatal volume loss. Fear was associated with additional atrophy of the right insula and left and right lateral orbitofrontal cortex. Even in early HD there is a wide-ranging impairment in recognition of negative emotions denoting 'threat'. Our findings implicate a generic fronto-subcortical network in the pathogenesis of these emotion recognition deficits.

Purpose of reviewPatients presenting with features of Huntington's disease but lacking the causative genetic expansion can be challenging diagnostically. The differential diagnosis of such Huntington's disease phenocopy syndromes has not recently been reviewed.Recent findingsCohort studies have established the relative frequencies of known Huntington's disease phenocopy syndromes, whereas newly described ones have been characterized genetically, clinically, radiologically and pathologically.SummaryAbout 1% of suspected Huntington's disease cases emerge as phenocopy syndromes. Such syndromes are clinically important in their own right but may also shed light on the pathogenesis of Huntington's disease. Huntington's disease produces a range of clinical phenotypes, and the range of syndromes that may be responsible for Huntington's disease phenocopies is correspondingly wide. Cohort studies have established that, while the majority of phenocopy patients remain undiagnosed, in those patients where a genetic diagnosis is reached the commonest causes are SCA17, Huntington's disease-like syndrome 2 (HDL2), familial prion disease and Friedreich's ataxia. We review the features of the reported genetic causes of Huntington's disease phenocopy syndromes, including HDL1-3, SCA17, familial prion disease, spinocerebellar ataxias, dentatorubral-pallidoluysian atrophy, chorea-acanthocytosis and iron-accumulation disorders. We present an evidence-based framework for the genetic testing of Huntington's disease phenocopy cases.

Huntington's disease (HD) causes widespread CNS changes and systemic abnormalities including endocrine and immune dysfunction. HD biomarkers are needed to power clinical trials of potential treatments. We used multiplatform proteomic profiling to reveal plasma changes with HD progression. Proteins of interest were evaluated using immunoblotting and ELISA in plasma from 2 populations, CSF and R6/2 mice. The identified proteins demonstrate neuroinflammation in HD and warrant further investigation as possible biomarkers.

Huntington disease is devastating to patients and their families - with autosomal dominant inheritance, onset typically in the prime of adult life, progressive course, and a combination of motor, cognitive and behavioural features. The disease is caused by an expanded CAG trinucleotide repeat (of variable length) in HTT, the gene that encodes the protein huntingtin. In mutation carriers, huntingtin is produced with abnormally long polyglutamine sequences that confer toxic gains of function and predispose the protein to fragmentation, resulting in neuronal dysfunction and death. In this Primer, we review the epidemiology of Huntington disease, noting that prevalence is higher than previously thought, geographically variable and increasing. We describe the relationship between CAG repeat length and clinical phenotype, as well as the concept of genetic modifiers of the disease. We discuss normal huntingtin protein function, evidence for differential toxicity of mutant huntingtin variants, theories of huntingtin aggregation and the many different mechanisms of Huntington disease pathogenesis. We describe the genetic and clinical diagnosis of the condition, its clinical assessment and the multidisciplinary management of symptoms, given the absence of effective disease-modifying therapies. We review past and present clinical trials and therapeutic strategies under investigation, including impending trials of targeted huntingtin-lowering drugs and the progress in development of biomarkers that will support the next generation of trials. For an illustrated summary of this Primer, visit: http://go.nature.com/hPMENh.

Research and patient communities are firmly interdependent. Engaged patient communities provide biological samples and data that drive discoveries which, in turn, fuel the development of novel therapies. Historically, Huntington's disease (HD) has benefited from trusting interactions between scientists and patients. However, even for HD, communication between the research and patient communities is suboptimal. The web platform HDBuzz was created to rectify this situation by providing accurate, accessible information on the latest HD research to patients and their supporters.

The known genetic cause of Huntington's disease (HD) has fueled considerable progress in understanding its pathobiology and the development of therapeutic approaches aimed at correcting specific changes linked to the causative mutation. Among the most promising is reducing expression of mutant huntingtin protein (mHTT) with RNA interference or antisense oligonucleotides; human trials are now being planned. Zinc-finger transcriptional repression is another innovative method to reduce mHTT expression. Modulation of mHTT phosphorylation, chaperone upregulation, and autophagy enhancement represent attempts to alter cellular homeostasis to favor removal of mHTT. Inhibition of histone deacetylases (HDACs) remains of interest; recent work affirms HDAC4 as a target but questions the assumed centrality of its catalytic activity in HD. Phosphodiesterase inhibition, aimed at restoring synaptic function, has progressed rapidly to human trials. Deranged cellular signaling provides several tractable targets, but specificity and complexity are challenges. Restoring neurotrophic support in HD remains a key potential therapeutic approach. with several approaches being pursued, including brain-derived neurotrophic factor (BDNF) mimesis through tyrosine receptor kinase B (TrkB) agonism and monoclonal antibodies. An increasing understanding of the role of glial cells in HD has led to several new therapeutic avenues, including kynurenine monooxygenase inhibition, immunomodulation by laquinimod, CB2 agonism, and others. The complex metabolic derangements in HD remain under study, but no clear therapeutic strategy has yet emerged. We conclude that many exciting therapeutics are progressing through the development pipeline, and combining a better understanding of HD biology in human patients, with concerted medicinal chemistry efforts, will be crucial for bringing about an era of effective therapies.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene. Both central and peripheral innate immune activation have been described as features of the disease. Isolated human HD monocytes have been shown to produce more cytokines upon LPS stimulation compared to control monocytes. Understanding alterations in the signalling cascades responsible and activated by this increase in pro-inflammatory cytokine production is crucial in understanding the molecular basis of this phenomenon. Here we investigated the signalling cascade most commonly activated by pro-inflammatory cytokines such as IL-6 - the JAK/STAT signalling cascade. Using flow cytometry, we show that one out of three key transcription factors activated by JAK/STAT signalling is altered in primary human HD innate immune cells, suggesting that this pathway may only play a minor, additive role in the immune cell dysfunction in HD.

There is a need for biomarkers of onset and progression in Huntington's disease (HD), as current outcome measures lack the reliability to enable the efficient conduct of disease-modifying trials. Neurofilament heavy chain (NfH) is a neuron-specific protein for the neuro-axonal compartment that has been proposed as a marker for axonal injury, degeneration and loss and its clinical use as a biomarker has been suggested in several neurodegenerative diseases. We used an enzyme-linked immunosorbent assay to quantify NfH levels in plasma in control subjects, premanifest HD mutation carriers and subjects with early and moderate manifest HD. We found no correlation between plasma NfH level and disease stage, or calculated parameters based on CAG repeat length, the major determinant of disease course in HD, and no evidence that NfH may be a predictor of disease onset. We conclude that plasma NfH concentration is not a useful biomarker of onset or progression in HD.

Around 1 per cent of patients in whom Huntington’s disease (HD) is suspected clinically lack the genetic mutation that causes HD. Such patients, referred to as having HD look-alike syndromes, HD phenocopies, or HD-like disorders, present a diagnostic challenge. This chapter offers a definition of HD look-alikes and reviews the causes and features of HD look-alike syndromes, including HD-like syndromes 1, 2 and 3, familial prion disease, , spinocerebellar ataxias 17, 1, 2 and 3, dentatorubro-pallidoluysian atrophy (DRPLA), brain iron accumulation disorders including pantothenate kinase associated neurodegeneration (PKAN) and neuroferritinopathy, choreoacanthocytosis, MacLeod syndrome, Wilson’s disease, Friedreich’s ataxia, mitochondrial disease, and benign hereditary chorea, and considers possible acquired causes. The evidence for the relative frequencies of each genetic cause is reviewed. The yield from exhaustive genetic investigation of such patients is only 2 per cent, which is important when it comes to genetic counselling. We propose a rational framework for the investigation of HD look-alike patients based on genetic frequencies and associated clinical features. The exclusion of treatable causes is a top priority. Expert genetic counselling and multidisciplinary care via a neurogenetics clinic remain the mainstay of care for such patients.

Background With several clinical trials in progress and more expected to launch in the next few years exploring novel therapeutic approaches for treating Huntington’s disease, biomarkers are needed to evaluate target engagement, efficacy and disease progression. Cerebrospinal fluid (CSF) is ideal for assessing HD biomarkers, due to its proximity to the brain. There is currently no high-quality repository of CSF from well-characterised HD gene expansion carriers spanning the disease spectrum. Aims Now underway, HDClarity is a multisite, multinational initiative that aims to establish the largest, highest-quality repository of CSF from well-characterised HD mutation carriers and matched controls, to expedite research into biomarkers and evaluate pathways to enable development of novel treatments for HD. Methods/techniques CSF and blood samples will be collected at up to 30 sites using a standardised protocol. Careful collection of clinical and phenotypic data on each donor will enable us to appropriately select subsets of samples for each set of experimental assays. HDClarity uses a custom data capture system built upon the Enroll-HD Platform to identify participants and collect standardised data. HDClarity will recruit up to 600 participants from six cohorts: Healthy controls Early Pre-manifest HD Late Pre-manifest HD Early Manifest HD Moderate Manifest HD Advanced Manifest HD Participants attend two study visits: a Screening Visit and a Sampling Visit. Some participants are invited to return for an optional repeat sampling visit 4–8 weeks later. Custom biosample kits are supplied by BioRep to supply all equipment for standardised CSF and plasma collection and processing. BioRep is also the sample biorepository. In one usage, the sample collection will be assayed to determine whether the kynurenine pathway (KP) is dysregulated in HD. It will also enable the further development and validation of assays to measure huntingtin protein in CSF. The biorepository will enable the continued evaluation of potential novel biomarkers. A CSF Consortium will provide scientific oversight into the use of samples and data. HDClarity is sponsored by University College London and coordinated by UCL Huntington’s disease Centre. It is funded and supported by CHDI Foundation, Inc. For more information or to enquire about establishing an HDClarity clinical site, please email the Chief Investigator (e.wild@ucl.ac.uk)

Background Huntington’s disease (HD) is a complex neurodegenerative condition that calls for a multifaceted approach to patient care. Multidisciplinary team (MDT) meetings are one tool by which the expertise of multiple professionals can be focused into the care of a patient, combining the knowledge and expertise required to deliver the best management plan. Aims To estimate the time and monetary costs of a HD MDT meeting held after a specialist HD clinic, and its value to patient care. Methods This study was authorised by the department’s Audit Lead, as stipulated by the UCLH/UCL NHS Trust, London, UK. Data were prospectively retrieved from HD MDT meetings at the National Hospital for Neurology and Neurosurgery from February to June 2016. To ascertain cost, at each meeting, staff members registered their name, position and time spent to prepare the meeting. All patients attending the HD Multidisciplinary Specialist Clinic were included in this study; the time spent to discuss each patient was recorded, as was age, gender and diagnostic stage. To evaluate the value, the number and type of changes to management plans, performed as a result of the MDT discussion, were recorded. The cost per unit of time -- estimated based on midlevel salary for each of the healthcare professionals involved -- was multiplied by the time each staff member spent preparing and attending the meeting. The annual cost was computed by means of the average cost per patient, the frequency of the meetings (26 per year) and the average number of patients discussed per meeting. Results Six meetings, comprising 92 patients (mean age 52 years; 58% males; 15% pre-manifest, 52% early HD, 22% moderate HD, 11% advanced HD) were analysed. Each meeting had a median duration of 41.33 minutes, a median of 14.5 patients, and a mean total cost of 451 GBP. Each patient was discussed for an average of 2:34 minutes, costing 30 GBP, and no difference was found between gender, age or stage. The estimated annual cost of this MDT meeting was £11474 GBP. More than 40% of draft management plans experienced a change as a result of the MDT discussion, a cost of £12 per change of plan. Conclusions Our study demonstrates that HD MDT meetings bring significant value to the management plan of patients at a modest cost. Still, further multicentre outcome-focused studies are needed to ascertain cost-effectiveness.

Background Inflammation and neuronal cell death are involved in HD pathogenesis and biomarkers for these processes could better characterise disease progression and the response to specific interventions. Aims This exploratory work intended to study general inflammatory cytokines, microglial activation markers, and neuronal cell death markers in the cerebrospinal fluid (CSF) of HD patients. Methods We assayed CSF TNF-α, IL-1β, IL-6, IL-8, YKL-40, chitotriosidase, tau and NFL from 23 mutation carriers and 14 healthy controls. TNF-α, IL-1β, IL-6, IL-8 and YKL-40 were measured using a MSD antibody-based tetra-plex array with electrochemiluminiscence detection. Chitotriosidase was measured using an in-house enzyme activity assay. Tau and NFL were quantified using commercial ELISAs. Results TNF-α and IL-1β were below the limit of detection. Mutation carriers had higher YKL-40 (p = 0.003), chitotriasidase (p = 0.015), IL-6 (p = 0.041) and NFL (p = 4.61*10−7) than healthy controls. NFL was different between pre-manifest and manifest mutation carriers (p = 0.006). YKL-40 and NFL showed significant association with age, and YKL-40, IL-8, Tau and NFL displayed significant association with disease burden score. Age-adjusted YKL-40 significantly correlated with disease stage (p = 0.001), TFC score (r = −0.46, p = 0.003), and TMS (r = 0.59, p = 4.32*10−4). TMS remained significant after adjusting for disease burden (r = 0.49, p = 0.028). Age-adjusted NFL significantly correlated with disease stage (p = 6.07*10−5), TFC (r = −0.38, p = 0.005) and TMS (r = 0.47, p = 6.89*10−5). Conclusions CSF biomarkers of inflammation and neuronal cell death may be useful biomarkers for HD. In particular, YKL-40, IL-8, Tau and NFL may independently predict clinical phenotype and could be useful as biomarkers of disease activity and treatment response. Further investigation is needed to support our exploratory findings. Funding CHDI Foundation Inc, GSK, Medical Research Council UK, Swedish Research Council and the Wolfson Foundation.

Background and aims Huntington’s disease (HD) is an autosomal-dominant condition and defined by a triad of movement, cognitive, and psychiatric symptoms. However, some patients in whom HD is suspected do not carry the CAG expansion in the Huntingtin gene (HTT). These cases, with symptoms on the HD spectrum, but without the HTT expansion, are called HD phenocopy syndromes. Their most frequent known cause has recently been identified as C9orf72, but recessive conditions can also mimic HD. Next generation sequencing technologies (NGS) facilitate the simultaneously screening of genes linked to other neurodegenerative conditions. Methods We applied a validated 17-gene NGS dementia panel (PRNP, PSEN1, PSEN2, APP, GRN, MAPT, TREM2, CHMP2B, CSF1R, FUS, ITM2B, NOTCH3, SERPINI1, SQSTM1, TARDBP, TYROBP and VCP) combined with PCR-based assessments of the C9orf72 and PRNP expansions to the UCL HD phenocopy cohort (n = 444). We classified mutations by likelihood of pathogenicity and compared with clinical data, including HD-likeness and family history. Results In the cohort, 7.2% of all patients displayed the complete triad of symptoms, and for 46.9% of these a relevant family history was reported. A further 32.7% presented with 2/3 of the triad, 20.3% of these had a relevant family history. Overall, a relevant family history was reported for 24% of patients. In the 409 cases processed so far, yet to be tested for the C9orf72 and PRNP expansions, 4.5% of patients were found to carry a (likely) deleterious variant, a further 4.1% carried a potentially deleterious variant and 7.9% carried a higher-risk allele. Conclusions A custom panel provides affordable high quality sequencing. These panels can now help identify mutations in genes not previously linked to HD phenocopies, and reduce the number of cases where even with a strong family history no genetic mutation is found. This ongoing work will help to provide answers to patients and families, who present with an HD syndrome without the diagnostic certainty of the HTT expansion.

Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by both neurological and systemic abnormalities. Immune activation is a well-established feature of the HD brain and we have previously demonstrated a widespread, progressive innate immune response detectable in plasma throughout the course of HD. In the present work we used multiplex ELISA to quantify levels of chemokines in plasma from controls and subjects at different stages of HD. We found an altered chemokine profile tracking with disease progression, with significant elevations of five chemokines (eotaxin-3, MIP-1β, eotaxin, MCP-1 and MCP-4) while three (eotaxin-3, MIP-1β and eotaxin) showed significant linear increases across advancing disease stages. We validated our results in a separate sample cohort including subjects at different stages of HD. Here we saw that chemokine levels (MCP-1 and eotaxin) correlated with clinical scores. We conclude that, like cytokines, chemokines may be linked to the pathogenesis of HD, and that immune molecules may be valuable in tracking and exploring the pathogenesis of HD.