Huntington's disease is a neurodegenerative disorder with relentless progression of symptoms and most patients die 15–20 years after diagnosis.1 An expanded cytosine-adenosine-guanine repeat in exon ...1 of the huntingtin gene leads to the accumulation of abnormal huntingtin protein aggregates in neurons, which is associated with a complex pathological cascade that causes progressive neuronal loss.1 Neuroinflammation has been implicated in the pathogenetic process of Huntington's disease, with mutation carriers having activation of microglia and astrocytes and a pro-inflammatory profile.2,3 In The Lancet Neurology, Ralf Reilmann and colleagues4 report results of the LEGATO-HD trial, which evaluated, for the first time in patients with Huntington's disease, the disease-modifying potential of the immunomodulator laquinimod. Interestingly, a substantial placebo response was observed for the UHDRS-TMS in the first 12 weeks of study follow-up and the effect of the placebo response in Huntington's disease clinical trials needs further study.5 In the secondary analysis of LEGATO-HD, laquinimod 1·0 mg was associated with a lesser percent change in caudate volume loss (least squares mean 3·10 SE 0·38) compared with placebo (4·86 0·38; least squares mean difference –1·76 95% CI –2·67 to –0·85; p=0·0002), alongside exploratory imaging outcome measures that showed other positive results for laquinimod 1·0 mg and 0·5 mg compared with placebo. Data on target engagement to support a definite and meaningful biological effect of laquinimod in the study are scarce: a 11C-PBR28 PET–CT imaging study in 11 LEGATO-HD study participants did not find a change in microglial activation with laquinimod compared with placebo.6 Reilmann and colleagues acknowledge that the caudate volume loss of 4·86% in the placebo group was larger than expected, and the changes in laquinimod groups were compatible with the natural history of Huntington's disease.7 A possible shorter time from diagnosis to baseline in the placebo group (32·3 months), compared with the laquinimod 0·5 mg group (45·8 months) and 1·0 mg group (41·5 months), with numerically similar baseline functional capacity, motor scores, and normalised caudate volume, raises the hypothesis that the placebo group could have had a more aggressive underlying pathology that was more reliably captured with neuroimaging, despite the randomisation process.
Huntington’s disease (HD) is a monogenic neurodegenerative disorder that presents with progressive motor, behavior, and cognitive symptoms leading to early disability and mortality. HD is caused by ...an expanded CAG repeats in exon 1 of the huntingtin (HTT) gene. The corresponding genetic test allows a clinical, definite diagnosis in life and the identification of a fully penetrant mutation carrier in a premanifest stage. In addition to the development of symptomatic treatments that attempt to address unmet care needs such as apathy, irritability, and cognition, novel therapies that target pathways specific to HD biology are being developed with the intent of slowing disease progression. Among these approaches, HTT protein lowering therapies hold great promise. There are currently active programs using antisense oligonucleotides (ASOs), RNA interference, small-molecule splicing modulators, and zinc-finger protein transcription factor. Except for ASOs and RNA interference approaches, the remaining therapeutic strategies are at a preclinical stage of development. While the current therapeutic landscape in HD may bring an unparalleled change in the lives of people with HD and their families with the first-ever disease-modifying therapy, the evaluation of these therapies requires novel tools that enable a more efficient and expedited discovery and evaluative process. Examples are biomarkers targeting the HTT protein to measure target engagement or disease progression and rating scales more sensitive to the earliest clinical changes. These tools will be instrumental in the next phase of disease-modifying clinical trials in HD likely to target the phenoconversion period of the disease, including the prodromal HD stage.
In the last half-century, Parkinson's disease (PD) has played a historical role in demonstrating our ability to translate preclinical scientific advances in pathology and pharmacology into highly ...effective clinical therapies. Yet, as highly efficacious symptomatic treatments were successfully developed and adopted in clinical practice, PD remained a progressive disease without a cure. In contrast with the success story of symptomatic therapies, the lack of translation of disease-modifying interventions effective in preclinical models into clinical success has continued to accumulate failures in the past two decades. The ability to stop, prevent or mitigate progression in PD remains the "holy grail" in PD science at the present time. The large number of high-quality disease modification clinical trials in the past two decades with its lessons learned, as well as the growing knowledge of PD molecular pathology should enable us to have a deeper understanding of the reasons for past failures and what we need to do to reach better outcomes. Periodic reviews and mini-reviews of the unsolved disease modification conundrum in PD are important, considering how this field is rapidly evolving along with our views and understanding of the possible explanations.
Despite the effectiveness of levodopa for treatment of Parkinson's disease (PD), prolonged usage leads to development of motor complications, most notably levodopa-induced dyskinesia (LID). Persons ...with PD and their physicians must regularly modify treatment regimens and timing for optimal relief of symptoms. While standardized clinical rating scales exist for assessing the severity of PD symptoms, they must be administered by a trained medical professional and are inherently subjective. Computer vision is an attractive, non-contact, potential solution for automated assessment of PD, made possible by recent advances in computational power and deep learning algorithms. The objective of this paper was to evaluate the feasibility of vision-based assessment of parkinsonism and LID using pose estimation.
Nine participants with PD and LID completed a levodopa infusion protocol, where symptoms were assessed at regular intervals using the Unified Dyskinesia Rating Scale (UDysRS) and Unified Parkinson's Disease Rating Scale (UPDRS). Movement trajectories of individual joints were extracted from videos of PD assessment using Convolutional Pose Machines, a pose estimation algorithm built with deep learning. Features of the movement trajectories (e.g. kinematic, frequency) were used to train random forests to detect and estimate the severity of parkinsonism and LID. Communication and drinking tasks were used to assess LID, while leg agility and toe tapping tasks were used to assess parkinsonism. Feature sets from tasks were also combined to predict total UDysRS and UPDRS Part III scores.
For LID, the communication task yielded the best results (detection: AUC = 0.930, severity estimation: r = 0.661). For parkinsonism, leg agility had better results for severity estimation (r = 0.618), while toe tapping was better for detection (AUC = 0.773). UDysRS and UPDRS Part III scores were predicted with r = 0.741 and 0.530, respectively.
The proposed system provides insight into the potential of computer vision and deep learning for clinical application in PD and demonstrates promising performance for the future translation of deep learning to PD clinical practices. Convenient and objective assessment of PD symptoms will facilitate more frequent touchpoints between patients and clinicians, leading to better tailoring of treatment and quality of care.
PURPOSE OF REVIEWHuntington's disease (HD) is an autosomal-dominant disorder caused by a pathological expansion of a trinucleotide repeat (CAG) on exon 1 of the huntingtin (HTT) gene. HD is ...characterized by the presence of chorea, alongside other hyperkinesia, parkinsonism and a combination of cognitive and behavioural features. Currently, there are no disease-modifying therapies (DMTs) for HD, and the only intervention(s) with approved indication target the treatment of chorea. This article reviews recent research on the clinical development of DMTs and newly developed tools that enhance clinical trial design towards a successful DMT in the future.RECENT FINDINGSHD is living in an era of target-specific drug development with emphasis on the mechanisms related to mutant Huntingtin (HTT) protein. Examples include antisense oligonucleotides (ASO), splicing modifiers and microRNA molecules that aim to reduce the levels of mutant HTT protein. After initial negative results with ASO molecules Tominersen and WVE-120101/ WVE-120102, the therapeutic landscape continues to expand, with various trials currently under development to document proof-of-concept and safety/tolerability. Immune-targeted therapies have also been evaluated in early-phase clinical trials, with promising preliminary findings. The possibility of quantifying mHTT in CSF, along with the development of an integrated biological staging system in HD are important innovations applicable to clinical trial design that enhance the drug development process. Although a future in HD with DMTs remains a hope for those living with HD, care partners and care providers, the therapeutic landscape is promising, with various drug development programs underway following a targeted approach supported by disease-specific biomarkers and staging frameworks.
We report a 68-year-old lady who presented with Huntington phenocopy with generalized chorea and was genetically proven to have Spinocerebellar ataxia (SCA)17. MRI Brain demonstrated motor band sign, ...which is most commonly reported in motor neuron disease. This is the first case of motor band sign with SCA 17 and highlights the widening spectrum of radiological signs in SCA 17.
•Case of SCA 17 with 41 CAG/CAA repeats presenting as a Huntington phenocopy.•First reported case of a Motor band sign seen in SCA 17.•Documents that motor band sign can be seen in a neurodegenerative disorder like SCA17.
Huntington disease (HD) is a rare genetic neurodegenerative condition. The availability of a genetic diagnosis makes HD an attractive model for the development of therapies that can delay or, at ...best, halt the progression of neurodegenerative conditions. Tetrabenazine and deutetrabenazine are the only treatment options with a formal indication (chorea) for this patient population.
Literature review on HD and clinical trials using the medical databases Pubmed, Web of Science, and clinical trial registries. Recent clinical trials conducted with the goal of disease-modification or new symptomatic treatment indications were included. Non-pharmacological interventions were excluded.
Therapeutic approaches aiming at disease-modification include huntingtin-lowering strategies, the modulation of huntingtin homeostasis and neuroinflammation. Huntingtin-lowering strategies are of particular interest by targeting the mRNA of the huntingtin (HTT) gene at the core of HD biology. Antisense oligonucleotides (ASO) are the only huntingtin-lowering strategies in clinical development. The initial results suggest that the first non-allele specific ASO was safe and associated with a reduction in the levels of mutated huntingtin protein (mHTT). Other clinical trials for disease-modification in HD have generated negative results or are ongoing. Assays to measure CSF mHTT and brain nuclear imaging specific to HD can support the rational development of these therapies. Novel symptomatic treatment indications explored in clinical trials include motor disability, irritability and apathy.
The years ahead are promising for novel and revolutionary therapies aimed at core disease mechanisms in HD. Clinical research platforms such as Enroll-HD are expected to potentiate the conduction of clinical trials in HD.
•The therapeutic development in Huntington disease is rich and promising.•Disease-specific therapies are being developed for the first time.•New symptomatic treatment indications have been recently evaluated.
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