The hunt for better treatments for Huntington's disease.

Huntington’s Disease (HD) is an autosomal dominant condition that typically presents in midlife with a combination of motor, cognitive and psychiatric problems along with sleep and metabolic abnormalities. It runs a clinical course over 15-20 years leading to death as patients become demented and bed bound. There are currently no proven disease modifying therapies for HD. While the recent work with anti-sense therapies (ASO) against huntingtin has generated much excitement they are yet to demonstrate a measurable change in disease progression. Furthermore, given they promise to “modify” and not “cure” HD patients we will still require adjunct symptomatic treatments, potentially for longer periods of time. Symptomatic therapies for HD do exist and are widely used for treating the chorea and some of the psychiatric aspects of the condition although the extent to which they work is variable1 and many experience significant side effects with them. Therefore, there is still a need to develop better symptomatic therapies, ideally with single drugs that can help treat more than one sign and symptom of this condition

Problems with Social Cognition and Decision-Making in Huntington's Disease: Why Is it Important?

Huntington's disease starts slowly and progresses over a 15-20 year period. Motor changes begin subtly, often going unnoticed by patients although they are typically visible to those close to them. At this point, it is the early non-motor problems of HD that arguably cause the most functional impairment. Approximately 65% of gene carriers will experience a reduction in their occupational level, and just under half will feel unable to manage their finances independently before a clinical diagnosis is made. Understanding what drives this impairment in activities of daily living is the key to helping people with HD to live more independently for longer, especially in early disease. Early cognitive decline is likely to play a contributory factor although few studies have looked directly at this relationship. Recently, it has been shown that along with the well documented dysexecutive syndrome seen in HD, changes in social cognition and decision-making are more common than previously thought. Furthermore, some of the early neuropathological and neurochemical changes seen in HD disrupt networks known to be involved in social functioning. In this review, we explore how HD changes the way individuals interact in a social world. Specifically, we summarise the literature on both classical and social decision-making (value-based decision-making in a social context) along with studies of theory of mind, empathy, alexithymia, and emotion recognition in HD. The literature specific to HD is discussed and supported by evidence from similar neurodegenerative disorders and healthy individuals to propose future directions and potential therapeutic avenues to be explored

The Clinical Features and Progression of Late-Onset Versus Younger-Onset in an Adult Cohort of Huntington's Disease Patients.

BACKGROUND: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that typically manifests between the ages of 30 and 50 years. However, the disease can present at any age, and phenotypic differences between younger and later-onset patients have received limited attention. OBJECTIVE: To compare clinical features of late- (>70 years of age) and younger-onset (<30 years of age) HD patients. METHODS: Patients presenting to our regional NHS HD clinic with new-onset manifest HD diagnosed over the age of 70 years (LoHD) (n = 18) were compared with a younger cohort who developed disease under the age of 30 years (YoHD) (n = 12). Rate of progression over time on standard cognitive and motor measures was compared. RESULTS: At first clinic presentation, both groups had the same total UHDRS scores. However, the LoHD group had higher chorea scores (F (1,28) = 6.52, p = 0.016), while the YoHD group had more dystonia (F (1,28) = 8.69, p = 0.006) and eye movement abnormalities (F (1,28) = 16.991, p < 0.001). The YoHD group also had a greater rate of motor progression, especially for bulbar measures (F (1, 28) = 6.96, p = 0.013) and bradykinesia (F (1, 28) = 7.99, p = 0.009). No differences were found in the rate of cognitive change (F (1,21) = 1.727, p = 0.203) nor functional capacity (F (1,28) = 1.388, p = 0.249) between the groups. CONCLUSION: Phenotypic differences between YoHD and LoHD patients were found in terms of initial presentation and rate of motor progression. This has implications for therapeutic trials involving HD patients of different ages, given their different clinical features and progression.SLM is funded by the Huntington’s Disease Association. RAB is supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, 146281 (the views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care) and MRC/WT Stem Cell Institute 203151/Z/16/Z

Apathy in Huntington’s Disease: A Review of the Current Conceptualization

Apathy is one of the most common psychiatric symptoms experienced by patients with Huntington’s disease (HD). It appears early, progresses with the disease course and has been shown to contribute significantly to caregiver burden. However, what is understood by apathy in HD is not clearly defined nor the underlying mechanisms responsible for it. In this review, we discuss the concept of apathy in the context of HD and propose that a consensus regarding its conceptualisation and subsequently its diagnostic criteria would significantly benefit the field. In order to undertake this work, we began by reviewing the existing literature on the definition and assessment of apathy in HD, its underlying neurobiological basis and its relationship to other related features such as abulia, anhedonia and alexithymia. In the context of HD, apathy could be described by a loss of or diminished motivation, emotion and goal-directed behaviour that is not best explained by motor or social constraints of the disease. However, there is an urgent need to better understand the characteristics of apathy specifically in HD, how they evolve across the disease course, and how they relate to central dopaminergic pathways. Only by undertaking such work can we hope to better understand this early and disabling aspect of HD.This work was supported by the NIHR funded Cambridge BRC

Robust algorithm for detecting floodwater in urban areas using Synthetic Aperture Radar images

Flooding is a major hazard in both rural and urban areas worldwide, but it is in urban areas that the impacts are most severe. High resolution Synthetic Aperture Radar (SAR) sensors are able to detect flood extents in urban areas during both day- and night-time. If obtained in near real-time, these flood extents can be used for emergency flood relief management or as observations for assimilation into flood forecasting models. In this paper a method for detecting flooding in urban areas using near real-time SAR data is developed and extensively tested under a variety of scenarios involving different flood events and different images. The method uses a SAR simulator in conjunction with LiDAR data of the urban area to predict areas of radar shadow and layover in the image caused by buildings and taller vegetation. Of the urban water pixels visible to the SAR, the flood detection accuracy averaged over the test examples was 83%, with a false alarm rate of 9%. The results indicate that flooding can be detected in the urban area to reasonable accuracy, but that this accuracy is limited partly by the SAR’s poor visibility of the urban ground surface due to shadow and layover

Antidopaminergic treatment is associated with reduced chorea and irritability but impaired cognition in Huntington’s disease (Enroll-HD)

Objectives: Alterations in dopamine neurotransmission underlie some of the clinical features of Huntington’s disease (HD) and as such are a target for therapeutic intervention, especially for the treatment of chorea and some behavioural problems. However, justification for such an intervention is mainly based on case reports and small open label studies and the effects these drugs have on cognition in HD remain unclear. Methods: In this study, we used the Enroll-HD observational database to assess the effects of antidopaminergic medication on motor, psychiatric and cognitive decline, over a 3-year period. We first looked at the annual rate of decline of a group of HD patients taking antidopaminergic medication (n=466) compared with an untreated matched group (n=466). The groups were matched on specified clinical variables using propensity score matching. Next, we studied a separate group of HD patients who were prescribed such medications part way through the study (n=90) and compared their rate of change before and after the drugs were introduced and compared this to a matched control group. Results: We found that HD patients taking antidopaminergic medication had a slower progression in chorea and irritability compared with those not taking such medications. However, this same group of patients also displayed significantly greater rate of decline in a range of cognitive tasks. Conclusion: In conclusion we found that antidopaminergic treatment is associated with improvements in the choreic movements and irritability of HD but worsens cognition. However, further research is required to prospectively investigate this and whether these are causally linked, ideally in a double-blind placebo-controlled trial

Visualising disease progression on multiple variables with vector plots and path plots.

BACKGROUND: It is often desirable to observe how a disease progresses over time in individual patients, rather than graphing group averages; and since multiple outcomes are typically recorded on each patient, it would be advantageous to visualise disease progression on multiple variables simultaneously. METHODS: A variety of vector plots and a path plot have been developed for this purpose, and data from a longitudinal Huntington's disease study are used to illustrate the utility of these graphical methods for exploratory data analysis. RESULTS: Initial and final values for three outcome variables can be easily visualised per patient, along with the change in these variables over time. In addition to the disease trajectory, the path individual patients take from initial to final observation can be traced. Categorical variables can be coded with different types of vectors or paths (e.g. different colours, line types, line thickness) and separate panels can be used to include further categorical or continuous variables, allowing clear visualisation of further information for each individual. In addition, summary statistics such as mean vectors, bivariate interquartile ranges and convex polygons can be included to assist in interpreting trajectories, comparing groups, and detecting multivariate outliers. CONCLUSION: Vector and path plots are useful graphical methods for exploratory data analysis when individual-level information on multiple variables over time is desired, and they have several advantages over plotting each variable separately.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Assimilating high resolution remotely sensed soil moisture into a distributed hydrologic model to improve runoff prediction

The susceptibility of a catchment to flooding during an extreme rainfall event is affected by its soil moisture condition prior to the event. A study to improve the state vector of a distributed hydrologic model by assimilating high resolution remotely sensed soil moisture is described. The launch of Sentinel-1 has stimulated interest in measuring soil moisture at high resolution suitable for hydrological studies using Synthetic Aperture Radars (SARs). The advantages of using SAR soil moisture in conjunction with land cover data are considered. These include the ability to reduce contamination of the surface soil signal due to vegetation, radar artefacts, mixed pixels and land cover classes not providing meaningful soil moistures. Results for 2008 using ASAR data showed that the assimilation of ASAR soil moisture values improved the predicted flows for all images. The improvement was less marked for 2007, probably because the antecedent soil moisture conditions were of reduced importance during the extreme flooding that occurred then. Particularly for 2008, the higher resolution of ASAR data improved predicted flows compared to low resolution ASCAT data that were not disaggregated and limited to the temporal frequency of ASAR. The method is likely to give better results with Sentinel-1 rather than ASAR data due to its higher temporal resolution

Floodwater detection in urban areas using Sentinel-1 and WorldDEM data

Remote sensing using Synthetic Aperture Radar (SAR) is an important tool for emergency flood incident management. At present operational services are mainly aimed at flood mapping in rural areas, as mapping in urban areas is hampered by the complicated backscattering mechanisms occurring there. A method for detecting flooding at high resolution in urban areas that may contain dense housing is presented. This largely uses remotely sensed data sets that are readily available on a global basis, including open-access Sentinel-1 SAR data, the WorldDEM Digital Surface Model (DSM), and open-access World Settlement Footprint data to identify urban areas. The method is a change detection technique that estimates flood levels in urban areas locally. It searches for increased SAR backscatter in the post-flood image due to double scattering between water (rather than unflooded ground) and adjacent buildings, and reduced SAR backscatter in areas away from high slopes. Areas of urban flooding are detected by comparing an interpolated flood level surface to the DSM. The method was tested on two flood events that occurred in the UK during the storms of Winter 2019-20. High urban flood detection accuracies were achieved for the event in moderate density housing. The accuracy reduced for the event in dense housing, when street widths became comparable to the DSM resolution, though would still be useful for incident management. The method has potential for operational use for detecting urban flooding in near real-time on a global basis