Publications by authors named "Filipe B Rodrigues"

51 Publications

Growth and renal function dynamics of renal oncocytomas in patients on active surveillance.

BJU Int 2021 May 28. Epub 2021 May 28.

Division of Surgery and Interventional Science, University College London, London, UK.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bju.15499DOI Listing
May 2021

Botulinum toxin type A versus anticholinergics for cervical dystonia.

Cochrane Database Syst Rev 2021 04 14;4:CD004312. Epub 2021 Apr 14.

Laboratory of Clinical Pharmacology and Therapeutics, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.

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. Before BtA, anticholinergics were the most widely accepted treatment.

Objectives: To compare the efficacy, safety, and tolerability of BtA versus anticholinergic drugs in adults with cervical dystonia.

Search Methods: We searched the Cochrane Movement Disorders' Trials Register to June 2003, screened reference lists of articles and conference proceedings to September 2018, and searched CENTRAL, MEDLINE, and Embase, with no language restrictions, to July 2020.

Selection Criteria: Double-blind, parallel, randomised trials (RCTs) of BtA versus anticholinergic drugs 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 and quality of the evidence. We resolved disagreements by consensus or by consulting a third review author. If enough data had been available, we were to perform meta-analyses using a random-effects model for the comparison of BtA versus anticholinergic drugs to estimate pooled effects and corresponding 95% confidence intervals (95% CI). 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 one RCT of moderate overall risk of bias (as multiple domains were at unclear risk of bias), which included 66 BtA-naive participants with cervical dystonia. Two doses of BtA (Dysport; week 0 and 8; mean dose 262 to 292 U) were compared with daily trihexyphenidyl (up to 24 mg daily). The trial was sponsored by the BtA producer. BtA reduced cervical dystonia severity by an average of 2.5 points (95% CI 0.68 to 4.32) on the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) severity subscale 12 weeks after injection, compared to trihexyphenidyl. More participants reported adverse events in the trihexyphenidyl treatment group (76 events), compared with the BtA group (31 events); however, the difference in dropouts due to adverse events was inconclusive between groups. There was a decreased risk of dry mouth, and memory problems with BtA, but the differences were inconclusive between groups for the other reported side effects (blurred vision, dizziness, depression, fatigue, pain at injection site, dysphagia, and neck weakness).

Authors' Conclusions: We found very low-certainty evidence that BtA is more effective, better tolerated, and safer than trihexyphenidyl. We found no information on a dose-response relationship with BtA, differences between BtA formulations or different anticholinergics, the utility of electromyography-guided injections, or the duration of treatment effect.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/14651858.CD004312.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092669PMC
April 2021

Kynurenine pathway metabolites in cerebrospinal fluid and blood as potential biomarkers in Huntington's disease.

J Neurochem 2021 Jul 5;158(2):539-553. Epub 2021 May 5.

UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, UK.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jnc.15360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375100PMC
July 2021

Brain-derived neurotrophic factor in cerebrospinal fluid and plasma is not a biomarker for Huntington's disease.

Sci Rep 2021 Feb 10;11(1):3481. Epub 2021 Feb 10.

UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK.

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. We quantified 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) 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. We conclude that 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-83000-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876124PMC
February 2021

The use of wearable/portable digital sensors in Huntington's disease: A systematic review.

Parkinsonism Relat Disord 2021 02 12;83:93-104. Epub 2021 Jan 12.

UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, UK. Electronic address:

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.parkreldis.2021.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957324PMC
February 2021

Mutant huntingtin and neurofilament light have distinct longitudinal dynamics in Huntington's disease.

Sci Transl Med 2020 12;12(574)

UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London WC1B 5EH, UK.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.abc2888DOI Listing
December 2020

Botulinum toxin type A therapy for hemifacial spasm.

Cochrane Database Syst Rev 2020 11 19;11:CD004899. Epub 2020 Nov 19.

Laboratory of Clinical Pharmacology and Therapeutics, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.

Background: This is an update of a Cochrane Review, first published in 2005. Hemifacial spasm (HFS) is characterised by unilateral, involuntary contractions of the muscles innervated by the facial nerve. It is a chronic disorder, and spontaneous recovery is very rare. The two treatments routinely available are microvascular decompression and intramuscular injections with botulinum toxin type A (BtA).

Objectives: To compare the efficacy, safety, and tolerability of BtA versus placebo in people with HFS.

Search Methods: We searched CENTRAL, MEDLINE, Embase, reference lists of articles, and conference proceedings in July 2020. We ran the electronic database search, with no language restrictions, in July 2020.

Selection Criteria: Double-blind, parallel, randomised, placebo-controlled trials (RCTs) of BtA versus placebo in adults with HFS.

Data Collection And Analysis: Two review authors independently assessed records. We planned to select included studies, extract data using a paper pro forma, and evaluate the risk of bias. We resolved disagreements by consensus, or by consulting a third review author. We planned to perform meta-analyses. The primary efficacy outcome was HFS-specific improvement. The primary safety outcome was the proportion of participants with any adverse event.

Main Results: We found no parallel-group randomised controlled trials comparing BtA and placebo in HFS.

Authors' Conclusions: We did not find any randomised trials that evaluated the efficacy and safety of botulinum toxin type A in people with hemifacial spasm, so we are unable to draw any conclusions. Observational data show a strong association between BtA treatment and symptom improvement, and a favourable safety profile. While it is unlikely that future placebo-controlled RCTs will evaluate absolute efficacy and safety, they should address relevant questions for both people with HFS (such as long-term effects, quality of life, and other patient-reported outcomes), and clinicians (such as relative effectiveness of different BtA formulations and schemes of treatment) to better guide clinical practice.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/14651858.CD004899.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078498PMC
November 2020

Botulinum toxin type A therapy for blepharospasm.

Cochrane Database Syst Rev 2020 11 19;11:CD004900. Epub 2020 Nov 19.

Laboratory of Clinical Pharmacology and Therapeutics, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.

Background: This is an update of a Cochrane Review first published in 2005. Blepharospasm is the second most common form of focal dystonia. It is a disabling disorder, characterised by chronic, intermittent or persistent, involuntary eyelid closure, due to spasmodic contractions of the orbicularis oculi muscles. Currently, botulinum toxin type A (BtA) is considered the first line of therapy for this condition.

Objectives: To compare the efficacy, safety, and tolerability of BtA versus placebo in people with blepharospasm.

Search Methods: We searched Cochrane Movement Disorders' Trials Register, CENTRAL, MEDLINE, Embase, reference lists of included articles, and conference proceedings. We ran all elements of the search, with no language restrictions, in July 2020.

Selection Criteria: Double-blind, parallel, randomised, placebo-controlled trials (RCTs) of BtA versus placebo in adults with blepharospasm.

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 did not carry out any prespecified subgroup analyses. The primary efficacy outcome was improvement on any validated symptomatic rating scale. The primary safety outcome was the proportion of participants with any adverse event.

Main Results: We included three RCTs, assessed at low to moderate overall risk of bias, which randomised 313 participants with blepharospasm. Two studies excluded participants with poorer prior responses to BtA treatment, therefore, they included an enriched population with a higher probability of benefiting from this therapy. All trials were industry-funded. All RCTs evaluated the effect of a single BtA treatment session. BtA resulted in a moderate to large improvement in blepharospasm-specific severity, with a reduction of 0.93 points on the Jankovic Rating Scale (JRS) severity subscale at four to six weeks after injection (95% confidence interval (CI) 0.61 to 1.25; I² = 9%) compared to placebo. BtA was also resulted in a moderate to large improvement in blepharospasm-specific disability and blepharospasm-specific involuntary movements at four to six weeks after injection (disability: 0.69 JRS disability subscale points, 95% CI 0.18 to 1.19; I² = 74%; blepharospasm-specific involuntary movements: standardised mean difference (SMD) 0.79, 0.31 to 1.27; I² = 58%) compared to placebo. BtA did not show a risk of adverse events (risk ratio (RR) 1.18, 95% CI 0.87 to 1.60; I² = 0%). However, BtA increased the risk of vision complaints and eyelid ptosis (vision complaints: RR 5.73, 95% CI 1.79 to 18.36; I² = 51%; eyelid ptosis: RR 4.02, 95% CI 1.61 to 10.00; I² = 39%). There was no distinction between BtA and placebo in the number of participants who dropped out of the trial. A single trial estimated the duration of effects to be 10.6 weeks (range 6.1 to 19.1). We found no evidence supporting the existence of a clear dose-response relationship with BtA. We found no data reporting the impact of BtA on health-related quality of life, or the development of secondary non-responsiveness.

Authors' Conclusions: We are moderately certain that a single BtA treatment resulted in a clinically relevant reduction of blepharospasm-specific severity and disability, and have low certainty that it is well tolerated, when compared with placebo. There is low-certainty evidence that people treated with BtA are not at an increased risk of developing adverse events, though BtA treatment likely increases the risk of visual complaints and eyelid ptosis. 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, or the impact on quality of life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/14651858.CD004900.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094161PMC
November 2020

Botulinum toxin type A therapy for cervical dystonia.

Cochrane Database Syst Rev 2020 11 12;11:CD003633. Epub 2020 Nov 12.

Laboratory of Clinical Pharmacology and Therapeutics, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/14651858.CD003633.pub4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106615PMC
November 2020

Cerebrospinal fluid endo-lysosomal proteins as potential biomarkers for Huntington's disease.

PLoS One 2020 17;15(8):e0233820. Epub 2020 Aug 17.

UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233820PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430717PMC
October 2020

Strategies to minimize placebo effects in research investigations.

Int Rev Neurobiol 2020 9;153:49-70. Epub 2020 Jun 9.

Laboratory of Clinical Pharmacology and Therapeutics, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal; Instituto de Medicina Molecular, Lisbon, Portugal; CNS-Campus Neurológico Sénior, Torres Vedras, Portugal. Electronic address:

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/bs.irn.2020.04.002DOI Listing
June 2020

Biological and clinical characteristics of gene carriers far from predicted onset in the Huntington's disease Young Adult Study (HD-YAS): a cross-sectional analysis.

Lancet Neurol 2020 06 26;19(6):502-512. Epub 2020 May 26.

Huntington's Disease Centre, Department of Neurodegenerative disease, UCL Queen Square Institute of Neurology, University College London, London, UK; Dementia Research Institute at University College London, London, UK. Electronic address:

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 <0·05 deemed a significant result.

Findings: Data were obtained between Aug 2, 2017, and April 25, 2019. We recruited 64 young adults with preHD and 67 controls. Mean ages of participants were 29·0 years (SD 5·6) and 29·1 years (5·7) in the preHD and control groups, respectively. We noted no significant evidence of cognitive or psychiatric impairment in preHD participants 23·6 years (SD 5·8) from predicted onset (FDR 0·22-0·87 for cognitive measures, 0·31-0·91 for neuropsychiatric measures). The preHD cohort had slightly smaller putamen volumes (FDR=0·03), but this did not appear to be closely related to predicted years to onset (FDR=0·54). There were no group differences in other brain imaging measures (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<0·0001, =0·01, and =0·03, respectively). CSF NfL elevations were more likely in individuals closer to expected clinical onset (FDR <0·0001).

Interpretation: We report normal brain function yet a rise in sensitive measures of neurodegeneration in a preHD cohort approximately 24 years from predicted clinical onset. CSF NfL appears to be a more sensitive measure than plasma NfL to monitor disease progression. This preHD cohort is one of the earliest yet studied, and our findings could be used to inform decisions about when to initiate a potential future intervention to delay or prevent further neurodegeneration while function is intact.

Funding: Wellcome Trust, CHDI Foundation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1474-4422(20)30143-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254065PMC
June 2020

Huntington's Disease Clinical Trials Corner: April 2020.

J Huntingtons Dis 2020 ;9(2):185-197

UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, UK.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JHD-200002DOI Listing
April 2021

The risks of converting post-hoc findings into primary outcomes in subsequent trials.

Ann Transl Med 2019 Dec;7(Suppl 8):S337

Laboratory of Clinical Pharmacology and Therapeutics, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/atm.2019.09.105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976501PMC
December 2019

Characterizing White Matter in Huntington's Disease.

Mov Disord Clin Pract 2020 Jan 28;7(1):52-60. Epub 2019 Nov 28.

University College London Huntington's Disease Centre, Department of Neurodegenerative Disease University College London Queen Square Institute of Neurology, University College London London United Kingdom.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mdc3.12866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962665PMC
January 2020

Prognostic value of phrenic nerve conduction study in amyotrophic lateral sclerosis: Systematic review and meta-analysis.

Clin Neurophysiol 2020 01 11;131(1):106-113. Epub 2019 Nov 11.

Faculdade de Medicina-Instituto de Medicina Molecular, Universidade de Lisboa, Lisbon, Portugal; Department of Neurosciences and Mental Health, Centro Hospitalar Universitário LIsboa-Norte, Lisbon, Portugal. Electronic address:

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 = 55.9%; 338 participants). CMAP-amplitude showed a moderate positive correlation with FVC (r = 0.400, 95%CI = 0.226-0.550; I = 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 = 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clinph.2019.10.016DOI Listing
January 2020

Huntington's Disease Clinical Trials Corner: June 2019.

J Huntingtons Dis 2019 ;8(3):363-371

UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, UK.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JHD-199003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839470PMC
July 2020

Anti-TNF Drugs for Chronic Uveitis in Adults-A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Front Med (Lausanne) 2019 24;6:104. Epub 2019 May 24.

Department of Rheumatology, Hospital de Santa Maria, Lisbon, Portugal.

We aimed to assess efficacy and safety of anti-tumor necrosis factor (TNF) drugs for adult chronic non-infectious uveitis (NIU). CENTRAL, MEDLINE, and EMBASE, were searched from inception to January 2019. Double-masked randomized placebo-controlled trials, assessing any anti-TNF vs. best medical intervention/standard of care in adults with chronic NIU were considered. The PRISMA and SAMPL guidelines were followed. The risk of bias was assessed using the Cochrane risk of bias tool. Overall quality of the evidence was assessed according to GRADE. PROSPERO registration: #CRD42016039068. The primary efficacy and safety outcomes were preservation of visual acuity (VA) and withdrawals due to adverse events, respectively. Meta-analysis of efficacy analysis was not performed due to significant clinical heterogeneity between studies' population and interventions. A total of 1,157 references were considered and 3 studies were included. The overall risk of bias was moderate. In active NIU, adalimumab group showed an increased likelihood of VA preservation (risk ratio (RR) 1.75, 95%CI 1.32 to 2.32, = 217), whereas the etanercept group did not (RR 0.81, 95%CI 0.57 to 1.14, = 20). In inactive NIU, adalimumab was associated with increased likelihood of VA preservation (RR 1.31, 95%CI 1.12 to 1.53, = 226). The rate of adverse events did not differ between anti-TNF and control arms (RR 1.03, 95%CI 0.94 to 1.13, = 410). There is high quality evidence that adalimumab decreases the risk of worsening VA in active and inactive NIU and very low quality evidence that the risk of etanercept worsening VA in inactive NIU is not different from placebo. Moderate quality evidence suggests that anti-TNF agents are not different from placebo on the risk of study withdrawal.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmed.2019.00104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543521PMC
May 2019

Comparison of the Huntington's Disease like 2 and Huntington's Disease Clinical Phenotypes.

Mov Disord Clin Pract 2019 Apr 12;6(4):302-311. Epub 2019 Mar 12.

Division of Human Genetics National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, The University of the Witwatersrand Johannesburg South Africa.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mdc3.12742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476590PMC
April 2019

Managing treatment fluctuations in Parkinson disease: "On" again-, "off" again.

Neurology 2019 03 1;92(13):597-598. Epub 2019 Mar 1.

From the Department of Neurology (W.S.M.), University of Arkansas for Medical Sciences, Little Rock; UCL Huntington's Disease Centre (F.B.R.), UCL Queen Square Institute of Neurology, London, UK; Clinical Pharmacology Unit (F.B.R.), Instituto de Medicina Molecular, Lisbon; and Laboratory of Clinical Pharmacology and Therapeutics (F.B.R.), Faculty of Medicine, University of Lisbon, Portugal.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000007193DOI Listing
March 2019

Huntington's Disease Clinical Trials Corner: January 2019.

J Huntingtons Dis 2019 ;8(1):115-125

UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, UK.

In this edition of the Huntington's Disease Clinical Trials Corner we expand on the GENERATION-HD1 and PACE-HD trials, and we list all currently registered and ongoing clinical trials in Huntington's disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JHD-190001DOI Listing
March 2020

Cerebrospinal fluid flow dynamics in Huntington's disease evaluated by phase contrast MRI.

Eur J Neurosci 2019 06 19;49(12):1632-1639. Epub 2019 Feb 19.

UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, UK.

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 HTTCAG 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ejn.14356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6618296PMC
June 2019

Deep brain stimulation for dystonia.

Cochrane Database Syst Rev 2019 Jan 10;1:CD012405. Epub 2019 Jan 10.

Laboratório de Farmacologia Clínica e Terapêutica, Faculdade de Medicina de Lisboa, Avenida Professor Egas Moniz, Lisboa, Portugal, 1649-028.

Background: Dystonia is a painful and disabling disorder, characterised by painful, involuntary posturing of the affected body region(s). Deep brain stimulation is an intervention typically reserved for severe and drug-refractory cases, although uncertainty exists regarding its efficacy, safety, and tolerability.

Objectives: To compare the efficacy, safety, and tolerability of deep brain stimulation (DBS) versus placebo, sham intervention, or best medical care, including botulinum toxin and resective or lesional surgery, in adults with dystonia.

Search Methods: We identified studies by searching the CENTRAL, MEDLINE, Embase, three other databases, four clinical trial registries, four grey literature databases, and reference lists of included articles. We ran the last search of all elements of the search strategy, with no language restrictions, on 29 May 2018.

Selection Criteria: Double-blind, parallel, randomised, controlled trials (RCTs) comparing DBS with sham stimulation, best medical care, or placebo in adults with dystonia.

Data Collection And Analysis: Two independent review authors assessed records, selected included studies, extracted data onto a standardised (or prespecified) data extraction form, and evaluated the risk of bias. We resolved disagreements by consensus or by consulting a third review author. We conducted meta-analyses using a random-effects model, to estimate pooled effects and corresponding 95% confidence intervals (95% CI). We assessed the quality of the evidence with GRADE methods. The primary efficacy outcome was symptom improvement on any validated symptomatic rating scale, and the primary safety outcome was adverse events.

Main Results: We included two RCTs, enrolling a total of 102 participants. Both trials evaluated the effect of DBS on the internal globus pallidus nucleus, and assessed outcomes after three and six months of stimulation. One of the studies included participants with generalised and segmental dystonia; the other included participants with focal (cervical) dystonia. We assessed both studies at high risk for performance and for-profit bias. One study was retrospectively registered with a clinical trial register, we judged the second at high risk of detection bias.Low-quality evidence suggests that DBS of the internal globus pallidus nucleus may improve overall cervical dystonia-related symptoms (mean difference (MD) 9.8 units, 95% CI 3.52 to 16.08 units; 1 RCT, 59 participants), cervical dystonia-related functional capacity (MD 3.8 units, 95% CI 1.41 to 6.19; 1 RCT, 61 participants), and mood at three months (MD 3.1 units, 95% CI 0.73 to 5.47; 1 RCT, 61 participants).Low-quality evidence suggests that In people with cervical dystonia, DBS may slightly improve the overall clinical status (MD 2.3 units, 95% CI 1.15 to 3.45; 1 RCT, 61 participants). We are uncertain whether DBS improves quality of life in cervical dystonia (MD 3 units, 95% CI -7.71 to 13.71; 1 RCT, 57 participants; very low-quality evidence), or emotional state (MD 2.4 units, 95% CI -6.2 to 11.00; 1 RCT, 56 participants; very low-quality evidence).Low-quality evidence suggests that DBS of the internal globus pallidus nucleus may improve generalised or segmental dystonia-related symptoms (MD 14.4 units, 95% CI 8.0 to 20.8; 1 RCT, 40 participants), overall clinical status (MD 3.5 units, 95% CI 2.33 to 4.67; 1 RCT, 37 participants), physical functioning-related quality of life (MD 6.3 units, 95% CI 1.06 to 11.54; 1 RCT, 33 participants), and overall dystonia-related functional capacity at three months (MD 3.1 units, 95% CI 1.71 to 4.48; 1 RCT, 39 participants). We are uncertain whether DBS improves physical functioning-related quality of life (MD 5.0 units, 95% CI -2.14 to 12.14, 1 RCT, 33 participants; very low-quality evidence), or mental health-related quality of life (MD -4.6 units, 95% CI -11.26 to 2.06; 1 RCT, 30 participants; very low-quality evidence) in generalised or segmental dystonia.We pooled outcomes related to safety and tolerability, since both trials used the same intervention and comparison. We found very low-quality evidence of inconclusive results for risk of adverse events (relative risk (RR) 1.58, 95% 0.98 to 2.54; 2 RCTs, 102 participants), and tolerability (RR 1.86, 95% CI 0.16 to 21.57; 2 RCTs,102 participants).

Authors' Conclusions: DBS of the internal globus pallidus nucleus may reduce symptom severity and improve functional capacity in adults with cervical, segmental or generalised moderate to severe dystonia (low-quality evidence), and may improve quality of life in adults with generalised or segmental dystonia (low-quality evidence). We are uncertain whether the procedure improves quality of life in cervical dystonia (very low-quality evidence). We are also uncertain about the safety and tolerability of the procedure in adults with either cervical and generalised, or segmental dystonia (very-low quality evidence).We could draw no conclusions for other populations with dystonia (i.e. children and adolescents, and adults with other types of dystonia), or for other DBS protocols (i.e. other target nuclei or stimulation paradigms). Further research is needed to establish the long-term efficacy and safety of DBS of the internal globus pallidus nucleus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/14651858.CD012405.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353249PMC
January 2019

Rating Scales and Performance-based Measures for Assessment of Functional Ability in Huntington's Disease: Critique and Recommendations.

Mov Disord Clin Pract 2018 Jul-Aug;5(4):361-372. Epub 2018 May 9.

Department of Neurological Sciences Rush University Medical Center Chicago USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mdc3.12617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174516PMC
May 2018

Evaluation of mutant huntingtin and neurofilament proteins as potential markers in Huntington's disease.

Sci Transl Med 2018 09;10(458)

Huntington's Disease Centre, University College London (UCL) Institute of Neurology, London WC1N 3BG, UK.

Huntington's disease (HD) is a genetic progressive neurodegenerative disorder, caused by a mutation in the 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.aat7108DOI Listing
September 2018

Management of Small Renal Masses.

Radiology 2018 10 4;289(1):272-273. Epub 2018 Sep 4.

Division of Surgery and Interventional Science, University College London, London, England.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1148/radiol.2018181391DOI Listing
October 2018

Huntington's Disease Clinical Trials Corner: August 2018.

J Huntingtons Dis 2018 ;7(3):279-286

Huntington's Disease Centre, University College London, UK.

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).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JHD-189003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087448PMC
October 2019

Physician perception versus true efficacy of tetrabenazine for Huntington's disease.

Curr Med Res Opin 2018 09 19;34(9):1537-1538. Epub 2018 Jul 19.

a Huntington's Disease Centre , University College London , London , UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/03007995.2018.1490703DOI Listing
September 2018

Adverse events with botulinum toxin treatment in cervical dystonia: How much should we blame placebo?

Parkinsonism Relat Disord 2018 11 15;56:16-19. Epub 2018 Jun 15.

Laboratory of Clinical Pharmacology and Therapeutics, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal; Instituto de Medicina Molecular, Lisbon, Portugal; Center for Evidence-Based Medicine, Faculty of Medicine, University of Lisbon, Lisbon, Portugal; Portuguese Collaborating Centre of the IberoAmerican Cochrane Network-Cochrane Portugal Faculty of Medicine, University of Lisbon, Lisbon, Portugal.

Introduction: Botulinum toxin (BoNT) is the first line therapy for cervical dystonia (CD), with most patients receiving many treatment sessions, and so come to recognize and expect the benefits and harms of BoNT, making it difficult to separate which adverse events (AEs) are driven by BoNT and which come from patients' expectations.

Methods: Using the results of three Cochrane systematic reviews of randomized controlled trials (RCTs) we pooled results to calculate the risk of general and specific AEs associated with BoNT, and the proportion of AEs that cannot be pharmacologically attributed to BoNT.

Results: Fifteen RCTs, enrolling 1604 patients, were included. BoNT was associated with an increased risk of AEs, but 79% of this increased risk cannot be pharmacologically attributed to BoNT.

Conclusions: Patients with CD attach a considerable expectation of harm due to BoNT, reflected in the large proportion of non-pharmacologically-mediated AEs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.parkreldis.2018.06.017DOI Listing
November 2018

Biofluid Biomarkers in Huntington's Disease.

Methods Mol Biol 2018 ;1780:329-396

Huntington's Disease Centre, Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-1-4939-7825-0_17DOI Listing
February 2019
-->