Search

In this edition of the Huntington’s Disease Clinical Trials Corner we expand on GENERATION HD1, PRECISION-HD1 and PRECISION-HD2, SELECT-HD, and VIBRANT-HD trials, and list all currently registered and ongoing clinical trials in Huntington’s disease.

Background: Biomarkers 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. Objective: To investigate the safety and feasibility of research lumbar punctures (LP) in HD. Methods: HDClarity 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. Results: Of 448 participants screened, 398 underwent at least 1 sampling visit, of which 98.24% were successful (i.e., CSF was collected), amounting to 10,610 mL of CSF and 8,200 mL 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. Conclusion: HDClarity is the largest CSF collection initiative to support scientific research into HD and is now stablished 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.

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

Huntington’s disease (HD) is an autosomal dominant genetic neurodegenerative disease caused by a CAG expansion in theHuntingtin (HTT)gene, translating to an expanded polyglutamine tract in the huntingtin (HTT) protein. Age at disease onset is correlated to CAG repeat length, but varies by decades between individuals with identical repeat lengths. Genome-wide association studies link HD modification to DNA repair and mitochondrial health pathways. Recent clinical studies show elevated DNA damage in HD, even at the premanifest stage of disease. One of the major DNA repair nodes influencing neurodegenerative disease is the PARP pathway. Accumulation of poly ADP-ribose (PAR), produced by PARP1 and PARP2, has been implicated in the pathology of Alzheimer’s and Parkinson’s diseases, as well as autosomal recessive cerebellar ataxia. We report that HD mutation carriers have lower cerebrospinal fluid PAR levels than healthy controls, starting at the premanifest stage. Patient-derived fibroblasts have reduced PARP1/2 activity and elevated DNA damage, while elevated PAR levels are only revealed upon inhibition of PAR degradation. These phenotypes are rescued by moderate huntingtin level reduction via the huntingtin-lowering splice modulator drug, LMI070 (Branaplam). As a direct mechanism, we have defined a PAR-binding motif in huntingtin, detected huntingtin complexed with PARylated proteins in human cells during stress, and localized huntingtin to mitotic chromosomes upon inhibition of PAR degradation. Direct huntingtin PAR binding was measured by fluorescence polarization and visualized by atomic force microscopy. These results provide insight into a very early molecular mechanism of HD, suggesting possible targets in HD to design early preventive therapies.

OBJECTIVES To study the natural history of renal oncocytomas and address indications for intervention by determining how growth is associated with renal function over time, the reasons for surgery and ablation, and disease-specific survival. PATIENTS AND METHODS The study was conducted in a retrospective cohort of consecutive patients with renal oncocytoma on active surveillance reviewed at the Specialist Centre for Kidney Cancer at the Royal Free London NHS Foundation Trust (2012 to 2019). Comparison between groups was performed using Mann-Whitney U-tests and chi-squared tests. A mixed-effects model with a random intercept for patient was used to study the longitudinal association between tumour size and estimated glomerular filtration rate (eGFR). RESULTS Longitudinal data from 98 patients with 101 lesions were analysed. Most patients were men (68.3%) and the median (interquartile range [IQR]) age was 69 (13) years. The median (IQR) follow-up was 29 (26) months. Most lesions were small renal masses, and 24% measured over 4 cm. Over half (64.4%) grew at a median (IQR) rate of 2 (4) mm per year. No association was observed between tumour size and eGFR over time (P = 0.871). Nine lesions (8.9%) were subsequently treated. Two deaths were reported, neither were related to the diagnosis of renal oncocytoma. CONCLUSION Natural history data from the largest active surveillance cohort of renal oncocytomas to date show that renal function does not seem to be negatively impacted by growing oncocytomas, and confirms clinical outcomes are excellent after a median follow-up of over 2 years. Active surveillance should be considered the 'gold standard' management of renal oncocytomas up to 7cm.

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

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.

ObjectiveTo estimate the magnitude of the placebo and nocebo responses in chronic peripheral neuropathic pain (CNP) and explore possible associations with trial characteristics.MethodsWe searched CENTRAL, MEDLINE, and Embase for randomized controlled trials (RCTs) from inception to May 2020. We included placebo-controlled RCTs of ≥8 weeks investigating first-line pharmacological interventions for CNP. Primary endpoints were the placebo response, the proportion of patients receiving placebo with pain intensity reduction (PIR) ≥30% from baseline, and the nocebo response, the proportion of patients receiving placebo experiencing adverse events (AEs). Screening, data extraction, and bias assessment (with the Cochrane risk of bias tool) were conducted by independent reviewers. We pooled data using a random-effects model.ResultsWe included 50 trials, with a combined 5,693 participants allocated to placebo, conducted between 1998 and 2020. Overall, 38% of patients receiving placebo reported PIR≥30% (95% CI 34 to 42, I2=86%); 23% reported PIR≥50% (95% CI 20 to 26; I2=81%). 50% of patients receiving placebo reported AEs (95% CI 0.43 to 0.58; I2=97%); 2% reported serious AEs (95% CI 2 to 3; I2=58%). In patients receiving active interventions, the placebo response accounts for 75% of the treatment effect on PIR≥30%, and the nocebo response accounts for 75% of the AEs. Interpreted inversely, only 25% of responses and 25% of adverse events can be attributed to the intervention. Publication year positively correlated with PIR≥30% and negatively correlated with AEs. Female sex negatively correlated with AEs.ConclusionsThe placebo and nocebo responses in parallel-designed RCTs in CNP are substantial and should be considered in trial interpretation and in the design of future trials.

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.

Proton magnetic resonance spectroscopy is a non-invasive method of exploring cerebral metabolism. In Huntington’s disease, altered proton magnetic resonance spectroscopy-determined concentrations of several metabolites have been described; however, findings are often discrepant and longitudinal studies are lacking. Proton magnetic resonance spectroscopy metabolites may represent a source of biomarkers, thus their relationship with established markers of disease progression require further exploration to assess prognostic value and elucidate pathways associated with neurodegeneration. In a prospective single-site controlled cohort study with standardized collection of CSF, blood, phenotypic and volumetric imaging data, we used 3 T proton magnetic resonance spectroscopy in conjunction with the linear combination of model spectra method to quantify seven metabolites (total n-acetylaspartate, total creatine, total choline, myo-inositol, GABA, glutamate and glutathione) in the putamen of 59 participants at baseline (15 healthy controls, 15 premanifest and 29 manifest Huntington’s disease gene expansion carriers) and 48 participants at 2-year follow-up (12 healthy controls, 13 premanifest and 23 manifest Huntington’s disease gene expansion carriers). Intergroup differences in concentration and associations with CSF and plasma biomarkers; including neurofilament light chain and mutant Huntingtin, volumetric imaging markers; namely whole brain, caudate, grey matter and white matter volume, measures of disease progression and cognitive decline, were assessed cross-sectionally using generalized linear models and partial correlation. We report no significant groupwise differences in metabolite concentration at baseline but found total creatine and total n-acetylaspartate to be significantly reduced in manifest compared with premanifest participants at follow-up. Additionally, total creatine and myo-inositol displayed significant associations with reduced caudate volume across both time points in gene expansion carriers. Although relationships were observed between proton magnetic resonance spectroscopy metabolites and biofluid measures, these were not consistent across time points. To further assess prognostic value, we examined whether baseline proton magnetic resonance spectroscopy 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 revealed glutamine + glutamate to display a slow linear decrease over time in gene expansion carriers. Altogether, our findings show some evidence of reduced total n-acetylaspartate and total creatine as the disease progresses and 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 consistent group differences, inconsistency between baseline and follow-up, and lack of clear longitudinal change suggests that proton magnetic resonance spectroscopy metabolites have limited potential as Huntington’s disease biomarkers.

BACKGROUND Remote monitoring of Huntington disease (HD) signs and symptoms using digital technologies may enhance early clinical diagnosis and tracking of disease progression, guide treatment decisions, and monitor response to disease-modifying agents. Several recent studies in neurodegenerative diseases have demonstrated the feasibility of digital symptom monitoring. OBJECTIVE The aim of this study was to evaluate a novel smartwatch- and smartphone-based digital monitoring platform to remotely monitor signs and symptoms of HD. METHODS This analysis aimed to determine the feasibility and reliability of the Roche HD Digital Monitoring Platform over a 4-week period and cross-sectional validity over a 2-week interval. Key criteria assessed were feasibility, evaluated by adherence and quality control failure rates; test-retest reliability; known-groups validity; and convergent validity of sensor-based measures with existing clinical measures. Data from 3 studies were used: the predrug screening phase of an open-label extension study evaluating tominersen (NCT03342053) and 2 untreated cohorts—the HD Natural History Study (NCT03664804) and the Digital-HD study. Across these studies, controls (n=20) and individuals with premanifest (n=20) or manifest (n=179) HD completed 6 motor and 2 cognitive tests at home and in the clinic. RESULTS Participants in the open-label extension study, the HD Natural History Study, and the Digital-HD study completed 89.95% (1164/1294), 72.01% (2025/2812), and 68.98% (1454/2108) of the active tests, respectively. All sensor-based features showed good to excellent test-retest reliability (intraclass correlation coefficient 0.89-0.98) and generally low quality control failure rates. Good overall convergent validity of sensor-derived features to Unified HD Rating Scale outcomes and good overall known-groups validity among controls, premanifest, and manifest participants were observed. Among participants with manifest HD, the digital cognitive tests demonstrated the strongest correlations with analogous in-clinic tests (Pearson correlation coefficient 0.79-0.90). CONCLUSIONS These results show the potential of the HD Digital Monitoring Platform to provide reliable, valid, continuous remote monitoring of HD symptoms, facilitating the evaluation of novel treatments and enhanced clinical monitoring and care for individuals with HD.

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.

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.

BACKGROUND: Hemifacial spasm is characterised by unilateral involuntary contractions of muscles innervated by the facial nerve. The usual cause is a vessel touching the facial nerve near its origin from the brain stem. Although it is a benign condition it can cause significant cosmetic and functional disability. It is a chronic disease and spontaneous recovery is very rare. The two treatments routinely available are microvascular decompression and Botulinum Toxin type A (BtA) muscular injections. OBJECTIVES: To determine whether botulinum toxin (BtA) is an effective and safe treatment for hemifacial spasm. SEARCH METHODS: We searched the Cochrane Movement Disorders Group trials register, the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2004), MEDLINE (1977 to December 2003), EMBASE (1977 to December 2003), and reference lists of articles. We also contacted drug manufacturers and researchers in the field. SELECTION CRITERIA: Randomised studies comparing BtA with placebo in people with hemifacial spasm. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. Study authors were contacted for additional information. Adverse effects information was collected from the trials. MAIN RESULTS: We found only one small randomised, placebo‐controlled trial involving 11 people. It was a crossover trial during which patients underwent four sets of injections, comparing placebo with three different doses of BtA ‐ formulation Botox(r) (low dose: one‐half of the intermediate dose; intermediate dose; and high dose: twice the intermediate dose), and one of placebo. In this trial BtA was superior to placebo. AUTHORS' CONCLUSIONS: The findings of this single eligible trial support the results of large, open, case‐control studies showing a benefit rate between 76 and 100%. This effect size probably makes it very difficult to perform new large placebo controlled trials for hemifacial spasm. Despite the paucity of good quality controlled data, all the studies available suggest that BtA is effective and safe for treating hemifacial spasm. Future trials should explore technical factors such as the optimum treatment intervals, different injection techniques, doses, Bt types and formulations. Other issues include service delivery, quality of life, long‐term efficacy, safety, and immunogenicity. BtA should be compared with surgical microvascular decompression.

Background This is an update of a Cochrane Review first published in 2005. Cervical dystonia is the most common form of focal dystonia, and is a highly disabling movement disorder, characterised by involuntary, usually painful, head posturing. Currently, botulinum toxin type A (BtA) is considered the first line therapy for this condition. Objectives To compare the efficacy, safety, and tolerability of BtA versus placebo, in people with cervical dystonia. Search methods We searched Cochrane Movement Disorders' Trials Register, CENTRAL, MEDLINE, Embase, reference lists of articles, and conference proceedings in July 2020. All elements of the search, with no language restrictions, were last run in July 2020. Selection criteria Double-blind, parallel, randomised, placebo-controlled trials (RCTs) of BtA versus placebo in adults with cervical dystonia. Data collection and analysis Two review authors independently assessed records, selected included studies, extracted data using a paper pro forma, and evaluated the risk of bias. We resolved disagreements by consensus or by consulting a third review author. We performed meta-analyses using a random-effects model, for the comparison of BtA versus placebo, to estimate pooled effects and corresponding 95% confidence intervals (95% CI). We performed preplanned subgroup analyses according to BtA dose used, the BtA formulation used, and the use (or not) of guidance for BtA injections. The primary efficacy outcome was improvement in cervical dystonia-specific impairment. The primary safety outcome was the proportion of participants with any adverse event. Main results We included nine RCTs, with moderate, overall risk of bias, that included 1144 participants with cervical dystonia. Seven studies excluded participants with poorer responses to BtA treatment, therefore, including an enriched population with a higher probability of benefiting from this therapy. Only one trial was independently funded. All RCTs evaluated the effect of a single BtA treatment session, using doses from 150 U to 500 U of onabotulinumtoxinA (Botox), 120 U to 240 U of incobotulinumtoxinA (Xeomin), and 250 U to 1000 U of abobotulinumtoxinA (Dysport). BtA resulted in a moderate to large improvement from the participant's baseline clinical status, assessed by the investigators, with a mean reduction of 8.09 points in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS total score) at week four after injection (95% CI 6.22 to 9.96; I² = 0%) compared to placebo. This corresponded, on average, to a 18.4% improvement from baseline. The mean difference (MD) in TWSTRS pain subscore at week four was 2.11 (95% CI 1.38 to 2.83; I² = 0%) compared to placebo. Overall, both participants and clinicians reported an improvement of subjective clinical status. It was unclear if dropouts due to adverse events differed (risk ratio (RR) 2.51; 95% CI 0.42 to 14.94; I² = 0%) However, BtA treatment increased the risk of experiencing an adverse event (R) 1.23; 95% CI 1.05 to 1.43; I² = 28%). Neck weakness (14%; RR 3.40; 95% CI 1.19 to 9.71; I² = 15%), dysphagia (11%; RR 3.19; 95% CI 1.79 to 5.70; I² = 0%), and diffuse weakness or tiredness (8%; RR 1.80; 95% CI 1.10 to 2.95; I² = 0%) were the most common treatment-related adverse events. Treatment with BtA resulted in a decreased risk of dropouts. We have moderate certainty in the evidence across all of the aforementioned outcomes, with the exception of subjective assessment and tolerability, in which we have high confidence in the evidence. We found no evidence supporting the existence of a clear dose-response relationship between BtA and improvement in cervical dystonia-specific impairment, a destinction between BtA formulations, or a variation with use of EMG-guided injection for efficacy outcomes. Due to clinical heterogeneity, we did not pool health-related quality of life data, duration of clinical effect, or the development of secondary non-responsiveness. Authors' conclusions We are moderately certain in the evidence that a single BtA treatment session resulted in a clinically relevant reduction of cervical dystonia-specific impairment, and pain, and highly certain that it is well tolerated, compared with placebo. There is moderate-certainty evidence that people treated with BtA are at an increased risk of developing adverse events, most notably, dysphagia, neckweakness and diffuse weakness or tiredness. There are no data from RCTs evaluating the effectiveness and safety of repeated BtA injection cycles. There is no evidence from RCTs to allow us to draw definitive conclusions on the optimal treatment intervals and doses, the usefulness of guidance techniques for injection, the impact on quality of life, or the duration of treatment effect.

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.

SARS-CoV-2 has emerged as a novel human pathogen, causing clinical signs, from fever to pneumonia – COVID-19 – but may remain mild or even asymptomatic. To understand the continuing spread of the virus, to detect those who are and were infected, and to follow the immune response longitudinally, reliable and robust assays for SARS-CoV-2 detection and immunological monitoring are needed and have been setup around the world. We quantified immunoglobulin M (IgM), IgG and IgA antibodies recognizing the SARS-CoV-2 receptor-binding domain (RBD) or the Spike (S) protein over a period of five months following COVID-19 disease onset or in previously SARS-CoV-2 PCR-positive volunteers. We report the detailed setup to monitor the humoral immune response from over 300 COVID-19 hospital patients and healthcare workers, 2500 University staff and 187 post-COVID19 volunteers, and assessing titres for IgM, IgG and IgA. Anti-SARS-CoV-2 antibody responses followed a classic pattern with a rapid increase within the first three weeks after symptoms. Although titres reduce from approximately four weeks, the ability to detect SARS-CoV-2 antibodies remained robust for five months in a large proportion of previously virus-positive screened subjects. Our work provides detailed information for the assays used, facilitating further and longitudinal analysis of protective immunity to SARS-CoV-2. Moreover, it highlights a continued level of circulating neutralising antibodies in most people with confirmed SARS-CoV-2, at least up to five months after infection.

Placebo-controlled trials are the research standard to evaluate new interventions for which there is no standard of care. While lessening performance and detection bias, such design provides a direct mode of comparison against the probed intervention. Still, using placebo arms may pose new challenges to the design, conduct and analysis of clinical trials. This is particularly relevant in circumstances of non-additivity between the therapeutic and the placebo effects, if the outcome of interest has floor or ceiling effects, or when the predicted effect size of the intervention is large and leads to small sample sizes. There are several possible strategies to mitigate the confounding effects of the placebo, each relevant to specific clinical trial designs. This chapter puts into context the new challenges created by the placebo effect, discusses possible ways around them, and explores the future of the field.

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.

Placebo-controlled trials are the research standard to evaluate new interventions for which there is no standard of care. While lessening performance and detection bias, such design provides a direct mode of comparison against the probed intervention. Still, using placebo arms may pose new challenges to the design, conduct and analysis of clinical trials. This is particularly relevant in circumstances of non-additivity between the therapeutic and the placebo effects, if the outcome of interest has floor or ceiling effects, or when the predicted effect size of the intervention is large and leads to small sample sizes. There are several possible strategies to mitigate the confounding effects of the placebo, each relevant to specific clinical trial designs. This chapter puts into context the new challenges created by the placebo effect, discusses possible ways around them, and explores the future of the field.

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).

Limitation of functional ability is a major feature of Huntington's disease (HD). The International Parkinson and Movement Disorder Society (MDS) commissioned the appraisal of the use and clinimetric properties of clinical measures of functional ability that have been applied in HD studies and trials to date, to make recommendations regarding their use based on standardized criteria. After a systematic literature search, we included a total of 29 clinical measures grouped into two categories: (1) performance-based measures (e.g., balance, walking, and reaching/grasping), and (2) rating scales. Three performance-based measures are rated as "recommended": the Tinetti Mobility Test for screening of fall risk and for severity assessment of mobility in patients with manifest HD (up to stage III); the Berg Balance Scale for severity of balance impairment; and the Six-Minute Walk Test for assessment of walking endurance (severity) in HD subjects with preserved ambulation. No rating scale targeting functional ability reached a "recommended" status either for screening or severity measurement. The main challenges identified in this review include applying widely accepted conceptual frameworks to the identified measures, the lack of validation of clinical measures to detect change over time, and absence of validated measures for upper limb function. Furthermore, measures of capacity or ability to perform activities of daily living had ceiling effects in people with early and pre-manifest HD. We recommend that the MDS prioritize the development of new scales that capture small, but meaningful changes in function over time for outcome assessment in clinical trials, particularly in earlier stages of HD.

© 2018 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd., Anti-tumour necrosis factor (TNF) drugs have been extensively used in non-infectious uveitis (NIU), when corticosteroids or conventional immunosuppressive drugs cannot adequately control inflammation or intolerable side-effects occur. However, systemic anti-TNF therapies are also associated with a myriad of side-effects. Therefore, intravitreal administration of anti-TNF biologics has been employed to minimize patient morbidity and systemic adverse effects, while maintaining therapeutic effectivity. We undertook a systematic review to determine evidence of efficacy and safety of intravitreal administration of anti-TNF drugs in adults with NIU. We conducted this systematic review according to the PRISMA guidelines. The protocol was registered with PROSPERO (CRD42016041946). We searched CENTRAL, MEDLINE and EMBASE, from inception to April 2017, as well as clinical trial registries and grey literature. The qualitative analysis included all studies of adult patients with a diagnosis of NIU and who received intravitreal anti-TNF drugs with a 4-week minimum follow-up. A total of 4840 references were considered for title and abstract screening. Seven full texts were screened, and five studies were considered for analysis. All studies were open-label, single-centre, prospective, non-randomized, interventional case series with a follow-up between 4 and 26 weeks, employing either adalimumab in two studies and infliximab in three. Three studies showed a treatment effect of anti-TNF intravitreal injections, while one study revealed short-term improvement and one study revealed no efficacy of anti-TNF intravitreal therapy. None of the studies reported ocular adverse effects but only two studies included electrophysiological assessment in the safety analysis and no study assessed systemic human anti-drug antibodies. The available evidence is not sufficiently robust to conclude about the clinical effectivity of intravitreal anti-TNF in NIU and so no recommendation can be made. In conclusion, intravitreal injection of anti-TNF antibodies remains a possible treatment option to be explored through robust clinical investigation.

The compromise of quality of life in Huntington's disease is a major issue, both for individuals with the disease as well as for their caregivers. The International Parkinson and Movement Disorder Society commissioned a review of the use and clinimetric validation status of measures used in Huntington's disease to assess aspects related with quality of life and to make recommendations on their use following standardized criteria. We included both patient‐centered measures (patient health‐related quality‐of‐life measures) and caregiver‐centered measures (caregiver quality‐of‐life measures). After conducting a systematic literature search, we included 12 measures of patient health‐related quality of life and 2 measures of caregiver quality of life. Regarding patient‐centered measures, the Medical Outcomes Study 36‐Item Short‐Form Health Survey is “recommended” as a generic assessment of health‐related quality of life in patients with Huntington's disease. The 12‐Item Short Form Health Survey, the Sickness Impact Profile, the 12‐item World Health Organization Disability Assessment Schedule, and the Huntington's Disease Health‐Related Quality of Life questionnaire are “suggested.” No caregiver‐centered quality‐of‐life measure obtained a “recommended” status. The Alzheimer's Carer's Quality of Life Inventory and the Huntington's Disease Quality of Life Battery for Carers are “suggested.” Recognizing that the assessment of patient health‐related quality of life can be challenging in Huntington's disease, as patients may lack insight and there is insufficient clinimetric testing of these scales, the committee concluded that further validation of currently available health‐related quality‐of‐life measures should be undertaken, namely, those Huntington's disease–specific health‐related quality‐of‐life measures that have recently been reported and used.

© 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.

© European Stroke Organisation 2017, Introduction: Cerebrovascular diseases are the most frequent risk factor for epilepsy in the elderly, and epileptic phenomenon following stroke is known to worsen the prognosis. Although electroencephalography is the gold standard epilepsy biomarker, it is rarely used in post-stroke studies, and the frequency of post-stroke epileptiform activity is still uncertain. Patients and methods: We analysed studies indexed to MEDLINE, Embase, Web of Science, PsycINFO and OpenGrey (up to March 2015), reporting post-stroke electroencephalographic epileptiform activity frequency in adults. Epileptiform activity was classified as ictal (electrographic seizures) and interictal (non-periodic spikes and sharp waves). Data selection, extraction and appraisal were done in duplicate. Random-effects meta-analysis was used to pool frequencies. Results: The pooled frequency of post-stroke ictal and interictal epileptiform activity was 7% (95% CI 3%–12%) and 8% (95% CI 4%–13%), respectively. The use of continuous electroencephalogram was not associated with an increased frequency of electrographic seizures (p ¼ 0.05), nor did the management setting (Intensive Care Unit versus nonIntensive Care Unit, p ¼ 0.31). However, studies with continuous electroencephalogram showed a higher frequency of interictal epileptiform activity (p ¼ 0.01). Discussion: This study provides the best available estimates of the frequency of post-stroke electroencephalographic epileptiform activity. Due to detection bias, it was not possible to correlate clinical and electrographic seizures. Conclusion: The frequency of ictal and interictal epileptiform activity in the electroencephalogram was comparable with previous frequency analyses of clinical seizures. The frequency of ictal epileptiform activity did not change with continuous record or clinical setting, while the frequency of interictal epileptiform activity increased with continuous record., The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the ‘‘2012 Research Grant in Cerebrovascular Diseases’’ (sponsor: Sociedade Portuguesa do AVC (SPAVC)/funder: Tecnifar).

Background Drug development in Huntington's disease (HD) is particularly challenging, and only two compounds are approved by the FDA. It is therefore essential to appraise drug development programs in order to understand the reasons for their failure during the early stages of development. Objectives To describe the landscape of HD therapeutic development and critically explore the causes of compound attrition in the different stages of drug development, from phase 1 to phase 4. Methods All HD clinical trials registered in the WHO International Clinical Trials Search Portal, from inception to May 2017, were analyzed. Two independent authors selected and extracted data. Success rate in a trial phase was calculated as the number of compounds that progressed to the next trial phase divided by the number of compounds in that phase. The overall success rate was calculated as the ratio between the number of compounds that receive regulatory approval and the total number of compounds. Results Ninety-nine trials assessing 41 compounds and eleven non-pharmacological interventions (devices and cell therapies) were identified. Twenty-four (24.2%) were phase 1 trials, 46 (46.5%) phase 2, 20 (20.2%) phase 3, and two (2.0%) phase 4. Sixty trials (60.6%) received industry sponsorship. The most frequently studied compounds were creatine, latrepirdine and pridopidine. The mean number of participants enrolled was 92.0 and the length of treatment was 262.9 days, and both increased from phase 1 to phase 3 trials. The success rate was 25.0% from phase 1 to phase 2, 19.4% from phase 2 to phase 3, and 14.3% from phase 3 to approval. The overall success rate was 3.5%. Conclusions Although HD is a rare condition, 99 HD trials were identified in a comprehensive clinical trial registry. We found a low success rate at earlier phases of drug-development and a very low trial success rate at later phases. There is a significant gap between drug discovery and development success rates that warrants careful appraisal and improvement.

Background: Huntington's disease (HD) is a rare and fatal inherited genetic disorder characterized by progressive motor, cognitive, and behavioral impairment. It leads to premature death, but data regarding advanced-stage disease are scarce. We sought to determine HD-associated survival, mortality, and causes and places of death. / Methods: Data from the European HD Network prospective study (REGISTRY) collected from 2001 through 2013 were used, including the Unified Huntington's Disease Rating Scale and death report forms. Group comparisons were performed using the t test or the χ2 test. Survival analyses were computed through Kaplan-Meier estimates of median survival. All tests were 2-sided with a significance level of P = 0.05. / Results: In total, 5164 participants were analyzed. The mean age at diagnosis was 49 years, and the mean age at death was 58 years. At the end of the study period, there were 533 deaths (10.3% of patients). Median survival was 24 years from diagnosis and 35 years from symptom onset. The most frequent causes of death were pneumonia (19.5%), other infections (6.9%), and suicide (6.6%). The most frequent places of death were the hospital (29.8%), the home (23.9%), and nursing houses (19.8%). / Conclusions: Patients with HD tend to die from the same conditions as patients with other neurodegenerative diseases. However, compared with nonhereditary Parkinson's disease and Alzheimer's disease, the median time from onset to death is longer, and the places of death are distinctive.

In this edition of the Huntington’s Disease Clinical Trials Corner we expand on the HD-DBS and on the TRIHEP3 trials, and we list all currently registered and ongoing clinical trials in Huntington’s disease.

Background Investigating early white matter (WM) change in Huntington's disease (HD) can improve our understanding of the way in which disease spreads from the striatum. Objectives We provide a detailed characterization of pathology‐related WM change in HD. We first examined WM microstructure using diffusion‐weighted imaging and then investigated both underlying biological properties of WM and products of WM damage including iron, myelin plus neurofilament light, a biofluid marker of axonal degeneration—in parallel with the mutant huntingtin protein. Methods We examined WM change in HD gene carriers from the HD–CSFcohort, baseline visit. We used standard‐diffusion magnetic resonance imaging to measure metrics including fractional anisotropy, a marker of WM integrity, and diffusivity; a novel diffusion model (neurite orientation dispersion and density imaging) to measure axonal density and organization; T1‐weighted and T2‐weighted structural magnetic resonance imaging images to derive proxy iron content and myelin‐contrast measures; and biofluid concentrations of neurofilament light (in cerebrospinal fluid (CSF) and plasma) and mutant huntingtin protein (in CSF). Results HD gene carriers displayed reduced fractional anisotropy and increased diffusivity when compared with controls, both of which were also associated with disease progression, CSF, and mutant huntingtin protein levels. HD gene carriers also displayed proxy measures of reduced myelin contrast and iron in the striatum. Conclusion Collectively, these findings present a more complete characterization of HD‐related microstructural brain changes. The correlation between reduced fractional anisotropy, increased axonal orientation, and biofluid markers suggest that axonal breakdown is associated with increased WM degeneration, whereas higher quantitative T2 signal and lower myelin‐contrast may indicate a process of demyelination limited to the striatum.

Objective To investigate whether increased fixed carbidopa doses of 65 or 105 mg (ODM-101/65 and ODM-101/105) in combination with 75, 100, 125, or 150 mg of levodopa and 200 mg of entacapone might improve “off” time in fluctuating Parkinson disease (PD) compared to the standard combination of 4:1 levodopa/carbidopa with the usual 200 mg of entacapone (LCE) during a 4-week treatment period. Methods This was a randomized, double-blind, double-dummy, active-controlled, crossover, multicenter, phase II, proof-of-concept study in patients with fluctuating PD. Results One hundred seventeen patients were randomized into the study (mean age 67.0 years; daily “off” time 5.3 hours; mean daily levodopa dose 610 mg). Carryover-adjusted mean changes from baseline “off” times were during ODM-101/65, −1.53 hours (p = 0.02 vs LCE), during ODM-101/105, −1.57 hours (p = 0.01 vs LCE), and during LCE −0.91 hours. Changes in daily “on” time without dyskinesia were 1.54 hours (p = 0.005 vs LCE), 1.38 hours (p = 0.0214 vs LCE), and 0.69 hours, respectively. Changes in “on” time with troublesome dyskinesia were

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ., Objective: Morphine is frequently used in acute coronary syndrome (ACS) due to its analgesic effect, it being recommended in the main cardiology guidelines in Europe and the USA. However, controversy exists regarding its routine use due to potential safety concerns. We conducted a systematic review of randomised-controlled trials (RCTs) and observational studies to synthesise the available evidence. Design: Systematic review and meta-analysis. Data sources: CENTRAL, MEDLINE, EMBASE and trial registries. Eligibility criteria for selecting studies: We included RCTs and observational studies evaluating the impact of morphine in cardiovascular outcomes or platelet reactivity measures. Data extraction and synthesis: Data were screened, extracted and appraised by two independent reviewers. The data were pooled results using a random-effects model. Outcomes included in-hospital mortality, major adverse cardiovascular events (MACE), platelet reactivity (using VerifyNow) and bleeding, reported as relative risk (RR) with 95%CI. We assessed the confidence in the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. We followed the Metaanalysis Of Observational Studies in Epidemiology and Preferred Reporting Items for Systematic Reviews and MetaAnalyses guidelines. Results: Five RCTs and 12 observational studies were included, enrolling 69 993 participants. Pooled results showed an increased risk of in-hospital mortality (RR 1.45 [95% CI 1.10 to 1.91], low GRADE confidence), MACE (RR 1.21, 95%CI 1.02 to 1.45) and an increased platelet reactivity at 1 and 2 hours (59.37 platelet reactivity units [PRU], 95%CI 36.04 to 82.71; 68.28 PRU, 95%CI 37.01 to 99.55, high GRADE confidence) associated with morphine. We found no significant difference in the risk of bleeding. We found no differences in subgroup analyses based on study design and ACS subtype. Conclusions: Morphine was associated with an increased risk of in-hospital mortality and MACE but the high risk of bias leads to low result confidence. There is high confidence that morphine decreases the antiplatelet effect of P2Y12 inhibitors., UID/BIM/50005/2019, project funded by Fundação para a Ciência e a Tecnologia (FCT)/ Ministério da Ciência, Tecnologia e Ensino Superior (MCTES) through Fundos do Orçamento de Estado.

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.

© 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved., Objectives: To assess the prognostic value of phrenic nerve conduction (PNC) in amyotrophic lateral sclerosis (ALS). Methods: We conducted a systematic review to identify studies reporting on PNC, and mortality and/or forced vital capacity (FVC) in patients with ALS. We searched Medline, EMBASE, and Web of Science. Two independent authors selected studies and extracted data. Risk of bias was assessed using the QUIPS tool. Hazard-ratios and correlation coefficients were pooled using a random effects generic inverse-variance model. Evidence quality was evaluated with GRADE. Results: In the pooled analysis, patients with CMAP-amplitude equal or below 0.4 mV are 2.021 more likely to die over the studied period (95%CI 1.161–3.522; I 2 = 55.9%; 338 participants). CMAP-amplitude showed a moderate positive correlation with FVC (r = 0.400, 95%CI = 0.226–0.550; I 2 = 69.77%; 381 participants). However, there was a weak negative correlation between CMAP-latency and FVC (r = 0.235; 95%CI = 0.447 to 0.024; I 2 = 15.92%; 112 participants). Conclusions: There is moderate-quality evidence that CMAP-amplitude of the PNC is correlated with FVC. Results favour a predictive value for mortality, but the risk of bias is high. Significance: PNC is a simple test that should be considered to assess respiratory function in ALS, especially in patients with bulbar involvement or cognitive impairment., We are grateful to GAPIC – Gabinete de Apoio à Investigação Científica, Tecnológica e Inovação (Scientific Research, Technology and Innovation Support Office), Faculty of Medicine, University of Lisbon, for the financial support provided to Claudia S Silva. This research was supported by UID/BIM/50005/2019, project funded by Fundação para a Ciência e a Tecnologia (FCT)/Ministério da Ciência, Tecnologia e Ensino Superior (MCTES) through Fundos do Orçamento de Estado.

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.

Multiple targeted therapeutics for Huntington's disease are now in clinical trials, including intrathecally delivered compounds. Previous research suggests that CSF dynamics may be altered in Huntington's disease, which could be of paramount relevance to intrathecal drug delivery to the brain. To test this hypothesis, we conducted a prospective cross‐sectional study comparing people with early stage Huntington's disease with age‐ and gender‐matched healthy controls. CSF peak velocity, mean velocity and mean flow at the level of the cerebral aqueduct, and sub‐arachnoid space in the upper and lower spine, were quantified using phase contrast MRI. We calculated Spearman's rank correlations, and tested inter‐group differences with Wilcoxon rank‐sum test. Ten people with early Huntington's disease, and 10 controls were included. None of the quantified measures was associated with potential modifiers of CSF dynamics (demographics, osmolality, and brain volumes), or by known modifiers of Huntington's disease (age and HTT CAG repeat length); and no significant differences were found between the two studied groups. While external validation is required, the attained results are sufficient to conclude tentatively that a clinically relevant alteration of CSF dynamics – that is, one that would justify dose‐adjustments of intrathecal drugs – is unlikely to exist in Huntington's disease.