Search

Converging lines of evidence from several models, and post‐mortem human brain tissue studies, support the involvement of the kynurenine pathway (KP) in Huntington's disease (HD) pathogenesis. Quantifying KP metabolites in HD biofluids is desirable, both to study pathobiology and as a potential source of biomarkers to quantify pathway dysfunction and evaluate the biochemical impact of therapeutic interventions targeting its components. In a prospective single‐site controlled cohort study with standardised collection of cerebrospinal fluid (CSF), blood, phenotypic and imaging data, we used high‐performance liquid‐chromatography to measure the levels of KP metabolites—tryptophan, kynurenine, kynurenic acid, 3‐hydroxykynurenine, anthranilic acid and quinolinic acid—in CSF and plasma of 80 participants (20 healthy controls, 20 premanifest HD and 40 manifest HD). We investigated short‐term stability, intergroup differences, associations with clinical and imaging measures and derived sample‐size calculation for future studies. Overall, KP metabolites in CSF and plasma were stable over 6 weeks, displayed no significant group differences and were not associated with clinical or imaging measures. We conclude that the studied metabolites are readily and reliably quantifiable in both biofluids in controls and HD gene expansion carriers. However, we found little evidence to support a substantial derangement of the KP in HD, at least to the extent that it is reflected by the levels of the metabolites in patient‐derived biofluids., Converging lines of evidence from non‐human models support the involvement of the kynurenine pathway in Huntington's disease. However, evidence in living humans is limited. In a prospective study with standardised collection of cerebrospinal fluid and blood, we used high‐performance liquid‐chromatography to analyse this pathway. We concluded that the selected metabolites are readily and reliably quantifiable. Yet, we found little evidence to support a substantial derangement of the kynurenine pathway in Huntington's disease, at least to the extent that it is reflected by the levels of the metabolites in patient‐derived biofluids. 3‐HK, 3‐hydroxykynurenine; KYNA, kynurenic acid; QUIN, quinolinic acid.

In chronic neurological conditions, wearable/portable devices have potential as innovative tools to detect subtle early disease manifestations and disease fluctuations for the purpose of clinical diagnosis, care and therapeutic development. Huntington's disease (HD) has a unique combination of motor and non-motor features which, combined with recent and anticipated therapeutic progress, gives great potential for such devices to prove useful. The present work aims to provide a comprehensive account of the use of wearable/portable devices in HD and of what they have contributed so far. We conducted a systematic review searching MEDLINE, Embase, and IEEE Xplore. Thirty references were identified. Our results revealed large variability in the types of sensors used, study design, and the measured outcomes. Digital technologies show considerable promise for therapeutic research and clinical management of HD. However, more studies with standardized devices and harmonized protocols are needed to optimize the potential applicability of wearable/portable devices in HD., Highlights • Wearable/portable sensors have been proposed to detect and quantify manifestations of many neurodegenerative diseases. • No systematic review so far has examined their use in Huntington's disease (HD). • This work draws a broad picture of the digital wearable-based landscape in HD. • The utility of wearables in clinical practice and therapeutic research still needs to be proved. • Collaborative efforts are needed to further investigate their clinical use in HD.

Huntington disease (HD) is a neurodegenerative disease caused by CAG repeat expansion in the huntingtin gene (HTT) and involves a complex web of pathogenic mechanisms. Mutant HTT (mHTT) disrupts transcription, interferes with immune and mitochondrial function, and is aberrantly modified post-translationally. Evidence suggests that the mHTT RNA is toxic, and at the DNA level, somatic CAG repeat expansion in vulnerable cells influences the disease course. Genome-wide association studies have identified DNA repair pathways as modifiers of somatic instability and disease course in HD and other repeat expansion diseases. In animal models of HD, nucleocytoplasmic transport is disrupted and its restoration is neuroprotective. Novel cerebrospinal fluid (CSF) and plasma biomarkers are among the earliest detectable changes in individuals with premanifest HD and have the sensitivity to detect therapeutic benefit. Therapeutically, the first human trial of an HTT-lowering antisense oligonucleotide successfully, and safely, reduced the CSF concentration of mHTT in individuals with HD. A larger trial, powered to detect clinical efficacy, is underway, along with trials of other HTT-lowering approaches. In this Review, we discuss new insights into the molecular pathogenesis of HD and future therapeutic strategies, including the modulation of DNA repair and targeting the DNA mutation itself.

In this edition of the Huntington's Disease Clinical Trials Corner we expand on the UniQure AMT-130 and on the Neurocrine Biosciences KINECT-HD trials, and list all currently registered and ongoing clinical trials in Huntington's disease.

Magnetic resonance spectroscopy (MRS) is a non-invasive method of exploring cerebral metabolism. In Huntington’s disease, altered MRS-determined concentrations of several metabolites have been described; however, findings are often discrepant and longitudinal studies of metabolite trajectory are lacking. MRS metabolites may represent a valuable source of biomarkers, thus their relationship with established biofluid and structural imaging markers of disease progression require further exploration to assess prognostic value and elucidate biochemical pathways associated with neurodegeneration. In a prospective single-site controlled cohort study with standardised collection of CSF, blood, phenotypic and imaging data, we used MRS to evaluate metabolic profiles in the putamen of 56 participants at baseline (15 healthy controls, 15 premanifest and 26 manifest gene expansion carriers) and at 2-year follow-up. Intergroup differences and associations with established measures were assessed cross-sectionally using generalized linear models and partial correlation, controlling for age and CAG repeat length. We report no significant groupwise differences in metabolite concentration but found several metabolites to be associated with measures of disease progression; however, only two relationships were replicated across both time points, with total Creatine (creatine + phosphocreatine) and myo-inositol displaying significant associations with reduced caudate volume. Although relationships were observed between MRS metabolites and biofluid measures, these were not consistent across time points. To further assess prognostic value of the metabolites, we examined whether baseline MRS values, or rate of change, predicted subsequent change in established measures of disease progression. Several associations were found but were inconsistent across known indicators of disease progression. Finally, longitudinal mixed effects models, controlling for age, revealed no significant change in metabolite concentration over time in gene expansion carriers. Altogether, our findings show some interesting cross-sectional associations between select metabolites, namely total creatine and myo-inositol, and markers of disease progression, potentially highlighting the proposed roles of neuroinflammation and metabolic dysfunction in disease pathogenesis. However, the absence of group differences, inconsistency between baseline and follow-up, and lack of clear longitudinal change over two years suggests that MRS metabolites have limited potential as biomarkers in Huntington’s disease.

STRUCTURED ABSTRACTBackgroundBiomarkers are needed to monitor disease progression, target engagement and efficacy in Huntington’s disease (HD). Cerebrospinal fluid (CSF) is an ideal medium to research such biomarkers due to its proximity to the brain.ObjectivesTo investigate the safety and feasibility of research lumbar punctures (LP) in HD.MethodsHDClarity (NCT02855476) is an ongoing international biofluid collection initiative built on the Enroll-HD platform, where clinical assessments are recorded. It aims to recruit 1,200 participants. Biosamples are collected following an overnight fast: blood via venipuncture and CSF via LP. Participants are healthy controls and HD gene expansion carriers across the disease spectrum. We report on monitored data from February 2016 to September 2019.ResultsOf 448 participants screened, 398 underwent at least 1 sampling visit, of which 98.24% were successful (i.e. CSF was collected), amounting to 10,610mL of CSF and 8,200mL of plasma. In the total 572 sampling visits, adverse events were reported in 24.13%, and headaches of any kind and post-LP headaches in 14.86% and 12.24%, respectively. Frequencies were less in manifest HD; gender, age, body mass index and disease burden score were not associated with the occurrence of the events in gene expansion carriers. Headaches and back pain were the most frequent adverse events.ConclusionsHDClarity is the largest CSF collection initiative to support scientific research into HD and is now established as a leading resource for HD research. Our data confirm that research LP in HD are feasible and acceptable to the community, and have a manageable safety profile.

Introduction\ud Despite being genetically inherited, it is unclear how non-genetic factors (e.g., substance use, employment) might contribute to the progression and severity of Huntington's disease (HD).\ud \ud Methods\ud We used propensity score (PS) weighting in a large (n = 2914) longitudinal dataset (Enroll-HD) to examine the impact of education, employment status, and use of tobacco, alcohol, and recreational and therapeutic drugs on HD progression. Each factor was investigated in isolation while controlling for 19 other factors to ensure that groups were balanced at baseline on potential confounders using PS weights. Outcomes were compared several years later using doubly robust models.\ud \ud Results\ud Our results highlighted cases where modifiable (non-genetic) factors - namely light and moderate alcohol use and employment - would have been associated with HD progression in models that did not use PS weights to control for baseline imbalances. These associations did not hold once we applied PS weights to balance baseline groups. We also found potential evidence of a protective effect of substance use (primarily marijuana use), and that those who needed antidepressant treatment were likely to progress faster than non-users.\ud \ud Conclusions\ud Our study is the first to examine the effect of non-genetic factors on HD using a novel application of PS weighting. We show that previously-reported associated factors – including light and moderate alcohol use – are reduced and no longer significantly linked to HD progression after PS weighting. This indicates the potential value of PS weighting in examining non-genetic factors contributing to HD as well as in addressing the known biases that occur with observational data.

Juvenile-onset Huntington’s disease (JoHD) is a rare, particularly devastating form of Huntington’s Disease (HD) for which clinical diagnosis is challenging and robust outcome measures are lacking. Neurofilament light protein (NfL) in plasma has emerged as a prognostic biomarker for adult-onset HD. We report that plasma NfL is elevated in JoHD and premanifest HD mutation-carrying children. Quantifying plasma NfL may improve clinical diagnosis and therapeutic trial design in the pediatric population.

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.

Brain-derived neurotrophic factor (BDNF) is implicated in the survival of striatal neurons. BDNF function is reduced in Huntington’s disease (HD), possibly because mutant huntingtin impairs its cortico-striatal transport, contributing to striatal neurodegeneration. The BDNF trophic pathway is a therapeutic target, and blood BDNF has been suggested as a potential biomarker for HD, but BDNF has not been quantified in cerebrospinal fluid (CSF) in HD.BDNF in CSF and plasma in the HD-CSF cohort (20 pre-manifest and 40 manifest HD mutation carriers and 20 age and gender-matched controls) were quantified using conventional ELISAs and an ultra-sensitive immunoassay.BDNF concentration was below the limit of detection of the conventional ELISAs, raising doubt about previous CSF reports in neurodegeneration. Using the ultra-sensitive method, BDNF concentration was quantifiable in all samples but did not differ between controls and HD mutation carriers in CSF or plasma, was not associated with clinical scores or MRI brain volumetric measures, and had poor ability to discriminate controls from HD mutation carriers, and premanifest from manifest HD.BDNF in CSF and plasma is unlikely to be a biomarker of HD progression, and urge caution in interpreting studies where conventional ELISA was used to quantify CSF BDNF.

Objective Huntington’s disease is a rare, genetic, neurodegenerative disease characterized by a triad of cognitive, behavioral, and motor symptoms. The condition gradually results in increasing disability, loss of independence, and ultimately death. Our objective was to use United States claims data (which offer valuable insight into the natural history of disease) to compare the prevalent comorbidities of people with Huntington’s disease against matched controls with Parkinson’s disease or with no major neurodegenerative diseases (general population controls). We also assess medication use in people with Huntington’s disease. Methods This was a retrospective, observational study using data from the IBM MarketScan® Databases. Cases and controls were matched 1:1, and comorbidities were analyzed in each group during 2017. Medications were also assessed in the Huntington’s disease cohort. Eligible cases had ≥ 2 diagnostic codes for Huntington’s disease; controls had ≥ 2 codes for Parkinson’s disease (with no record of Huntington’s disease), or, for general population controls, no record of Huntington’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, or dementia. Results A total of 587 matched individuals were assessed in each cohort. Depression and anxiety were more common in Huntington’s disease versus Parkinson’s disease (odds ratios: 1.51 and 1.16, respectively). Other conditions more common in Huntington’s disease included dementia, communication/speech problems, dysphagia, and falls. The use of antidepressant (59.9%) and antipsychotic (39.5%) medications was frequent among Huntington’s disease cases. Interpretation These data highlight the prevalence of psychiatric, cognitive, communication, swallowing, and mobility problems in people with Huntington’s disease, underscoring the need for holistic expert care of these individuals.

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

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, but could help understand the natural history of the disease and how these biomarkers might help in therapeutic development and the clinic. In an 80-participant cohort over 24 months, mHTT in cerebrospinal fluid (CSF), and NfL in CSF and blood, had distinct longitudinal trajectories in HD mutation carriers compared with controls. Baseline analyte values predicted clinical disease status and 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 possesses prognostic value and is a valuable pharmacodynamic marker for huntingtin-lowering trials.

In the third edition of the Huntington's Disease Clinical Trials Corner we list all currently registered and ongoing clinical trials, expand on the SIGNAL trial (NCT02481674), and cover the recently finished CREST-E trial (NCT00712426).

Background: The measurement of disease-relevant biomarkers has become a major component of clinical trial design, but in the absence of rigorous clinical and analytical validation of detection methodology, interpretation of results may be misleading. In Huntington’s disease (HD), measurement of the concentration of mutant huntingtin protein (mHTT) in cerebrospinal fluid (CSF) of patients may serve as both a disease progression biomarker and a pharmacodynamic readout for HTT-lowering therapeutic approaches. We recently published the quantification of mHTT levels in HD patient CSF by a novel ultrasensitive immunoassay-based technology and here analytically validate it for use. / Objective: This work aims to analytically and clinically validate our ultrasensitive assay for mHTT measurement in human HD CSF, for application as a pharmacodynamic biomarker of CNS mHTT lowering in clinical trials. / Methods: The single molecule counting (SMC) assay is an ultrasensitive bead-based immunoassay where upon specific recognition, dye-labeled antibodies are excited by a confocal laser and emit fluorescent light as a readout. The detection of mHTT by this technology was clinically validated following established Food and Drug Administration and European Medicine Agency guidelines. / Results: The SMC assay was demonstrated to be accurate, precise, specific, and reproducible. While no matrix influence was detected, a list of interfering substances was compiled as a guideline for proper collection and storage of patient CSF samples. In addition, a set of recommendations on result interpretation is provided. / Conclusions: This SMC assay is a robust and ultrasensitive method for the relative quantification of mHTT in human CSF.

© 2017 – 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 License (CC-BY 4.0)., Clinical Trials Corner of Journal of Huntington’s Disease will regularly review ongoing and recently completed clinical trials in Huntington’s disease. In this inaugural issue, we list all currently registered and ongoing clinical trials, expand on LEGATO-HD and IONIS-HTTRx, and cover two recently finished trials: Amaryllis and Pride-HD.

Key PointsQuestionHow do levels of neurofilament light in cerebrospinal fluid (cNfL) compare between neurological conditions and with healthy controls? FindingsAmong 10 059 individuals in this systematic review and meta-analysis, cNfL was elevated in most neurological conditions compared with healthy controls, and the magnitude of the increase varies extensively. Although cNfL overlaps between most clinically similar conditions, its distribution did not overlap in frontotemporal dementia and other dementias or in Parkinson disease and atypical parkinsonian syndromes. MeaningThe cNfL is a marker of neuronal damage and may be useful to differentiate some clinically similar conditions, such as frontotemporal dementia from Alzheimer disease and Parkinson disease from atypical parkinsonian syndromes. This systematic review and meta-analysis assesses the associations of age, sex, and diagnosis with neurofilament light in cerebrospinal fluid and evaluates its potential in discriminating clinically similar conditions. ImportanceNeurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date. ObjectivesTo assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions. Data SourcesPubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC. Study SelectionStudies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex. Data Extraction and SynthesisIndividual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept. Main Outcome and MeasureThe cNfL levels adjusted for age and sex across diagnoses. ResultsData were collected for 10059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n=2795), dementias and predementia stages (n=4284), parkinsonian disorders (n=984), and HC (n=1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes. Conclusions and RelevanceThese data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.

Molecular markers derived from cerebrospinal fluid (CSF) represent an accessible means of exploring the pathobiology of Huntington’s disease (HD) in vivo. The endo-lysosomal/autophagy system is dysfunctional in HD, potentially contributing to disease pathogenesis and representing a potential target for therapeutic intervention. Several endo-lysosomal proteins have shown promise as biomarkers in other neurodegenerative diseases; however, they have yet to be fully explored in HD. We performed parallel reaction monitoring mass spectrometry analysis (PRM-MS) of multiple endo-lysosomal proteins in the CSF of 60 HD mutation carriers and 20 healthy controls. Using generalised linear models controlling for age and CAG, none of the 18 proteins measured displayed significant differences in concentration between HD patients and controls. This was affirmed by principal component analysis, in which no significant difference across disease stage was found in any of the three components representing lysosomal hydrolases, binding/transfer proteins and innate immune system/peripheral proteins. However, several proteins were associated with measures of disease severity and cognition: most notably amyloid precursor protein, which displayed strong correlations with composite Unified Huntington’s Disease Rating Scale, UHDRS Total Functional Capacity, UHDRS Total Motor Score, Symbol Digit Modalities Test and Stroop Word Reading. We conclude that although endo-lysosomal proteins are unlikely to have value as disease state CSF biomarkers for Huntington’s disease, several proteins demonstrate associations with clinical severity, thus warranting further, targeted exploration and validation in larger, longitudinal samples.

BACKGROUND: Huntington's disease like 2 (HDL2) is the most common Huntington's disease (HD) phenocopy in many countries and described as the phenocopy with the greatest resemblance to HD. The current clinical description of HDL2 is based on retrospective data. It is unknown whether HDL2 has clinical features that distinguish it from HD. OBJECTIVE: To describe the HDL2 phenotype and compare it to HD systematically. METHODS: A blinded cross‐sectional design was used to compare the HDL2 (n = 15) and HD (n = 13) phenotypes. African ancestry participants underwent assessments, including the Unified Huntington's Disease Rating Scale (UHDRS). The UHDRS motor component was video recorded and evaluated by blinded experts and the inter‐rater reliability calculated. RESULTS: Both groups were homogeneous in terms of demographics and disease characteristics. However, HDL2 patients presented three years earlier with more prominent dysarthria and dystonia. Raters could not distinguish between the two diseases with a high level of agreement. No significant differences in the TMS between HDL2 and HD were found. In both disorders, disease duration correlated with motor scores, with the exception of chorea. Psychiatric and cognitive scores were not significantly different between the groups. CONCLUSIONS: The HDL2 phenotype is similar to HD and is initially characterized by dementia, chorea, and oculomotor abnormalities, progressing to a rigid and bradykinetic state, suggesting the UHDRS is useful to monitor disease progression in HDL2. Although HDL2 patients scored higher on some UHDRS domains, this did not differentiate between the two diseases; it may however be emerging evidence of HDL2 having a more severe clinical phenotype.

Huntington's disease (HD) is a genetic progressive neurodegenerative disorder, caused by a mutation in the HTT gene, for which there is currently no cure. The identification of sensitive indicators of disease progression and therapeutic outcome could help the development of effective strategies for treating HD. We assessed mutant huntingtin (mHTT) and neurofilament light (NfL) protein concentrations in cerebrospinal fluid (CSF) and blood in parallel with clinical evaluation and magnetic resonance imaging in premanifest and manifest HD mutation carriers. Among HD mutation carriers, NfL concentrations in plasma and CSF correlated with all nonbiofluid measures more closely than did CSF mHTT concentration. Longitudinal analysis over 4 to 8 weeks showed that CSF mHTT, CSF NfL, and plasma NfL concentrations were highly stable within individuals. In our cohort, concentration of CSF mHTT accurately distinguished between controls and HD mutation carriers, whereas NfL concentration, in both CSF and plasma, was able to segregate premanifest from manifest HD. In silico modeling indicated that mHTT and NfL concentrations in biofluids might be among the earliest detectable alterations in HD, and sample size prediction suggested that low participant numbers would be needed to incorporate these measures into clinical trials. These findings provide evidence that biofluid concentrations of mHTT and NfL have potential for early and sensitive detection of alterations in HD and could be integrated into both clinical trials and the clinic.

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 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 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 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.

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).

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.

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.

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.

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 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.

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.

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.

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.

Many scientists and people from families affected by Huntington's disease prefer to avoid ‘the C-word’: cure. Acknowledging this, I still feel it is justifiable to describe Huntington's as the most curable incurable brain disorder. Everyone with HD has the same basic problem – a CAG expansion mutation in HTT, encoding a polyglutamine tract in the huntingtin protein (The Huntington's Disease Collaborative Research Group, 1993). Everyone with that problem will develop HD at some point, slowly succumbing to progressive cognitive, motor and psychiatric impairment. It is almost fully penetrant and truly dominant, and the genetic test is bleakly reliable. The more prevalent neurodegenerative diseases like Alzheimer's and Parkinson's lack this certainty: only a tiny minority of cases have a defined genetic cause. Therapeutic targets must be prosecuted on the balance of probability. In HD, we operate ‘beyond reasonable doubt’: mutant huntingtin is a smoking gun. Anything that cannot be connected to the mutation or protein may confidently be discarded. History has shown HD is an easy problem to define, for which it is surprisingly difficult to find solutions. Twenty-two years of research since the gene discovery in 1993 (see Fig. 1) has revealed much about huntingtin protein and its toxic twin, resulting in numerous genetically-accurate cell and animal models and theories of molecular and cellular pathogenesis – yielding multiple therapeutic targets (Ross et al., 2014, Wild and Tabrizi, 2014). Fig. 1 Some milestones on the road to huntingtin-lowering investigational therapies for HD patients. 1990, RNA interference is described after overexpression of pigmentation enzymes in petunia flowers (left) is seen to produce paradoxical reductions in pigment ... Based on our early understanding of its pathogenesis, the HD field tested an array of already-licensed neuroactive drugs (including baclofen, lamotrigine, riluzole and minocycline), plus a whole shelf of ‘nutraceuticals’ held to be generally good for neurons (creatine, coenzyme Q, fish oil and others). Nothing worked (Mestre et al., 2009). A failed drug does not imply a failed trial. Collectively, these experiences improved the field's ability to design and run trials that can give a definitive answer, and to prioritise therapeutic targets and generate comprehensive preclinical data to inform decisions about advancing to clinical trials. We also have at our disposal a new generation of drugs that take aim at the known cause of HD. 2005 saw the first attempt to ‘silence’ the HTT gene in an HD mouse model, using RNA interference. Originally discovered in petunia flowers, and eventually found to be a natural means of regulating post-transcriptional gene expression across species (Matzke and Matzke, 2004), ‘gene silencing’ as a therapeutic approach involves designing and synthesising an oligonucleotide molecule with a sequence complementary to the messenger RNA of the gene of interest. mRNA bound to the drug molecule is degraded by cellular enzymes, diminishing the manufacture of the target protein. Conceptually, the technique is as simple as turning off the water in an overflowing bathtub; but that does not mean it is easy to implement for a neurodegenerative disease – even one with a clear, dominant genetic cause. The mice whose brains were injected with the RNA interference compound did not just deteriorate more slowly – their motor problems improved, and regression of neuropathology was also seen (Harper et al., 2005). Similar improvements have been seen now with several such drugs in different model animals. These models may be imperfect but are the only current means by which preclinical efficacy can be judged. Meanwhile, a quiet revolution has been taking place in the field of HD biomarkers. The need for measures that can give an early, objective indication of progression or therapeutic effect is common to all neurodegenerative diseases. In HD, we can identify people destined to get the disease, but a major challenge is measuring whether a drug is working to prevent onset. By any established clinical measure, mutation carriers are indistinguishable from controls until they develop symptoms. So, large cohorts of patients and mutation carriers were assembled and studied over years, to determine what measurements were most reliable for predicting onset and progression. The result was a toolkit of imaging, clinical and cognitive biomarkers that can be used to facilitate clinical trials (Tabrizi et al., 2013). Last year, we reported the first quantification of mutant huntingtin protein in cerebrospinal fluid (CSF), and showed that its concentration predicts clinical features of HD. This is the smoking gun itself, released from the neurons it is killing (Wild et al., 2015). We now need to enlist large cohorts of well-characterised HD mutation carriers and study their CSF comprehensively: this is the aim of our nascent HDClarity study (http://hdclarity.net). In September 2015, the first dose of an antisense oligonucleotide drug – a chemically-modified single DNA strand – was injected into the CSF of a patient with HD (BBC News, 2015). The global trial, led by our centre at UCL, is designed to test the safety of the drug, IONIS-HTTRx, developed by Ionis Pharmaceuticals, aimed at suppressing production of huntingtin in the human brain (ClinicalTrials.gov, 2015). Among other measures, huntingtin will be quantified in CSF to look for evidence that the drug is engaging with its target. This trial marks a huge step towards treatments to improve the situation of HD-affected families. It owes its existence to decades in parallel pursuit of basic and clinical pathobiology, therapeutic development, biomarker discovery, clinical trials and patient education (e.g. http://hdbuzz.net). Testing the efficacy of this first huntingtin-lowering drug alone will take several years, and of course there may be setbacks ahead. It is to be hoped that whatever can be accomplished in HD will illuminate the global fight against neurodegenerative disease.

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.

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.