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Huntington’s disease (HD) is an inherited neurodegenerative disease characterised by neuropsychiatric symptoms, a movement disorder (most commonly choreiform) and progressive cognitive impairment. The diagnosis is usually confirmed through identification of an increased CAG repeat length in the huntingtin gene in a patient with clinical features of the condition. Though diagnosis is usually straightforward, unusual presentations can occur, and it can be difficult to know when someone has transitioned from being an asymptomatic carrier into the disease state. This has become increasingly important recently, with several putative disease-modifying therapies entering trials. A growing number of conditions can mimic HD, including rare genetic causes, which must be considered in the event of a negative HD genetic test. Patients are best managed in specialist multidisciplinary clinics, including when considering genetic testing. Current treatments are symptomatic, and largely directed at the chorea and neurobehavioural problems, although supporting trial evidence for these is often limited.

Functional dependency in basic activities of daily living (ADLs) is a key outcome in Parkinson's disease (PD). We aimed to define dependency in PD, using the original and MDS versions of the Unified Parkinson's Disease Rating Scale (UPDRS).We developed two algorithms to define dependency from items of UPDRS Part 2 and MDS-UPDRS Part 2 relating to basic ADLs (feeding, dressing, hygiene and walking, and getting out of a chair). We validated both algorithms using data from 1110 patients from six community-based PD incidence cohorts, testing concurrent validity, convergent validity, and predictive validity.Our optimal algorithm showed high specificity and moderate to high sensitivity versus SchwabEngland80% (specificity 95% [95% confidence interval (CI) 93-97] and sensitivity 65% [95% CI 55-73] at baseline; 88% [95% CI 85-91] and 85% [95% CI 79-97] respectively at five-years follow-up). Convergent validity was demonstrated by strong associations between dependency defined by the algorithm and cognition (MMSE), quality of life (PDQ39), and impairment (UPDRS part 3) (all p 0.001). Algorithm-defined dependency status also predicted mortality: HR for mortality in those dependent vs independent at baseline was 1.6 (95%CI 1.2-2.1) and in those dependent vs independent at five-years' follow-up was 2.2 (1.6-3.0).We have demonstrated the concurrent validity, convergent validity, and predictive validity of a UPDRS-/MDS-UPDRS-based algorithm to define functional dependency in PD. This can be used for studying dependency in any study where UPDRS or MDS-UPDRS part 2 data have been collected.

Objective To assess the claim that Parkinson's disease (PD) specifically reduces religiosity religious faith and spirituality. Methods A longitudinal case-control study over 12 months of spirituality in 42 patients with idiopathic PD and 39 disease controls matched for age, gender, educational attainment and disability. There was no selection on grounds of religious affiliation. Participants were assessed on the Beck Depression Inventory, Medical Outcomes Score (MOS), cognitive tests including Paired Associate Learning [PAL], One Touch Stocking [OTS]) and Stroop test. Tests of spirituality were the Brief Multidimensional Measure of Religiousness and Spirituality questionnaire (BMMRS), a Mystical Experiences Questionnaire (MEQ), and the Rivermead Life Goals Score, supplemented by qualitative interview methods. Results Over one year, as expected, mobility and cognition declined in the PD group. However, there was no significant change in scores of religiosity and spirituality scores in this group. Likewise, there were no subjective reports of a decrease of interest in religious faith or spirituality, although anecdotal accounts of decreasing mobility, loss of driving ability, increasing emotional lability and tiredness meant reduced participation in some religious and spiritual practices. However, over one year there was a significant fall in controls' religiosity score due mainly to a fall in 'religious practices' with no clear underlying reason. Conclusions Compared to non-neurological patients with similar disability, Parkinson's disease is not associated with a decline in religious faith or spirituality. Declining mobility and cognition in Parkinson's disease does not lead to diminished religiosity.

Objectives Radiation therapy is the treatment of choice for cats with sinonasal carcinomas. Different protocols have been described in the literature, though a clear consensus regarding the optimal protocol is lacking. The aim of the study was to describe the tolerability, efficacy and outcome of cats treated with a cyclical hypofractionated protocol. Methods Cats with histologically diagnosed sinonasal carcinomas in a single institution were retrospectively included. All patients were treated with a cyclical hypofractionated protocol (‘QUAD shot’ regime). Cats were treated with 4 Gray (Gy) delivered in four fractions within 48 h, with a minimum of 6 h between two treatments, and repeated every 3–4 weeks for a total dose of 48 Gy in three cycles. Results Seven cats met the inclusion criteria. Nasal discharge and sneezing were the most common presenting complaints. All cats presented with advanced stage of disease with CT examination (three with modified Adams stage 3 and four with stage 4). Clinical improvement was seen in six cats. Five cats had a follow-up CT; one had a complete response, two had partial responses, one had stable disease and one had progressive disease. Two cats were still alive at the time of writing while four were euthanased owing to tumour-related causes. The median overall survival time was 460 days. The 1-year survival time was 80% and the 2-year survival time was 0%. Severe acute or late toxicity was not reported. Conclusions and relevance This is the first report of a cyclical hypofractionated protocol in the veterinary literature that can provide prolonged survival in cats with advanced stage sinonasal carcinoma. Its use should be considered in patients when prolonged hospitalisation can be detrimental to quality of life, while still delivering a therapeutic total dose of radiation therapy.

Dysfunction of the central dopaminergic system is thought to contribute to some of the clinical features of Huntington's disease (HD), and dopamine (DA) receptor antagonists are commonly used to good effect in its treatment. It is well established that there is an early significant reduction in neuronal D2 receptors in HD, considered to be a compensatory response to increased dopaminergic activity. However, no studies have examined the expression of D2 receptors on astrocytes which is important given that these cells have been shown to play a role in the pathogenesis of HD, as well as express dopamine receptors and modulate DA homeostasis in the normal brain. We therefore sought to investigate the expression of D2 receptors on astrocytes in HD, and found them to be reduced in both the R6/1 HD mouse model, and in human post-mortem brain in comparison to controls, suggesting that astrocytes may be important in DA-dependent aspects of HD. Further studies are needed to determine the functional significance of this finding.

ObjectivesInsight is an important predictor of quality of life in Huntington’s disease and other neurodegenerative conditions. However, estimating insight with traditional methods such as questionnaires is challenging and subjected to limitations. This cross-sectional study experimentally quantified metacognitive insight into cognitive performance in Huntington’s disease gene carriers.MethodsWe dissociated perceptual decision-making performance and metacognitive insight into performance in healthy controls (n=29), premanifest (n=19) and early-manifest (n=10) Huntington’s disease gene carriers. Insight was operationalised as the degree to which a participant’s confidence in their performance was informative of their actual performance (metacognitive efficiency) and estimated using a computational model (HMeta-d’).ResultsWe found that premanifest and early-manifest Huntington’s disease gene carriers were impaired in making perceptual decisions compared with controls. Gene carriers required more evidence in favour of the correct choice to achieve similar performance and perceptual impairments were increased in those with manifest disease. Surprisingly, despite marked perceptual impairments, Huntington’s disease gene carriers retained metacognitive insight into their perceptual performance. This was the case after controlling for confounding variables and regardless of disease stage.ConclusionWe report for the first time a dissociation between impaired cognition and intact metacognition (trial-by-trial insight) in the early stages of a neurodegenerative disease. This unexpected finding contrasts with the prevailing assumption that cognitive deficits are associated with impaired insight. Future studies should investigate how intact metacognitive insight could be used by some early Huntington’s disease gene carriers to positively impact their quality of life.

Huntington's disease (HD) is a neurodegenerative disease in which cognitive and behavioural symptoms impair the performance of instrumental activities of daily living, including the handling of finances. We sought to determine the prevalence of financial dysfunction in HD, and the demographic and clinical predictors of such impairments.We analysed longitudinal data for pre-manifest gene carriers and HD patients from the Enroll-HD dataset. Financial dysfunction was determined by finance-related items in the Total Functional Capacity (TFC) and Functional Assessment (FA) scales. A binary logistical regression model was used to investigate the predictive value of demographic and clinical factors for the development of financial dysfunction.Financial impairment was found to be common in HD gene carriers, and over half required financial assistance within 5 years from diagnosis. Cognitive impairment, apathy, unemployment and disease severity predicted financial dysfunction in manifest patients. For pre-manifest patients, the predictors were proximity to disease onset and depression.Loss of financial autonomy is common in HD, and cognitive and psychiatric factors are important in its development. Clinicians must be vigilant to identify patients that may be vulnerable to financial exploitation.

Background Long‐term population‐representative data on motor fluctuations and levodopa‐induced dyskinesias in Parkinson's disease is lacking. Methods The Cambridgeshire Parkinson's Incidence from GP to Neurologist (CamPaIGN) cohort comprises incident PD cases followed for up to 13 years (n = 141). Cumulative incidence of motor fluctuations and levodopa‐induced dyskinesias and risk factors were assessed using Kaplan‐Meyer and Cox regression analyses. Results Cumulative incidence of motor fluctuations and levodopa‐induced dyskinesias was 54.3% and 14.5%, respectively, at 5 years and 100% and 55.7%, respectively, at 10 years. Higher baseline UPDRS‐total and SNCA rs356219(A) predicted motor fluctuations, whereas higher baseline Mini‐mental State Examination and GBA mutations predicted levodopa‐induced dyskinesias. Early levodopa use did not predict motor complications. Both early motor fluctuations and levodopa‐induced dyskinesias predicted reduced mortality in older patients (age at diagnosis >70 years). Conclusions Our data support the hypothesis that motor complications are related to the severity of nigrostriatal pathology rather than early levodopa use and indicate that early motor complications do not necessarily confer a negative prognosis. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Background Cognitive disturbances occur early in Huntington’s disease (HD) and place a significant burden on the lives of patients and family members. Whilst these impairments are typically attributed to deterioration of the frontal-striatal pathways, accumulating evidence suggests that hippocampal dysfunction may also contribute to such impairments. Here, we employ a novel spatial memory task that has previously been shown to elicit impairments in individuals with focal hippocampal lesions, as a means to further investigate the role of hippocampal dysfunction in HD. Method Sixty-four individuals participated in the study, including 32 healthy controls, 11 patients with diagnosed HD and 16 premanifest HD gene carriers. We also included an additional control group of 5 individuals with focal unilateral basal ganglia lesions. Participants undertook a task that measured perception and short-term spatial memory using computer-generated visual scenes. Results HD patients experienced significant impairments in spatial perception and memory, which strongly correlated with disease burden score (DBS). Premanifest gene carriers performed at a similar level to healthy controls throughout all aspects of the task indicating that the effects seen in the HD patients represent a deterioration in function. Interestingly, basal ganglia lesion patients were not impaired in any aspects of the task. Conclusion There is evidence of significant deficits in hippocampal-dependent spatial cognition in HD that cannot be explained as a function of degeneration to the basal ganglia. The impairments were greatest in individuals with higher DBSs, suggesting that deficits relate to the disease process in HD.

The production of extracellular vesicles (EV) is a ubiquitous feature of eukaryotic cells but pathological events can affect their formation and constituents. We sought to characterize the nature, profile and protein signature of EV in the plasma of Parkinson's disease (PD) patients and how they correlate to clinical measures of the disease. EV were initially collected from cohorts of PD (n = 60; Controls, n = 37) and Huntington's disease (HD) patients (Pre-manifest, n = 11; manifest, n = 52; Controls, n = 55) – for comparative purposes in individuals with another chronic neurodegenerative condition – and exhaustively analyzed using flow cytometry, electron microscopy and proteomics. We then collected 42 samples from an additional independent cohort of PD patients to confirm our initial results. Through a series of iterative steps, we optimized an approach for defining the EV signature in PD. We found that the number of EV derived specifically from erythrocytes segregated with UPDRS scores corresponding to different disease stages. Proteomic analysis further revealed that there is a specific signature of proteins that could reliably differentiate control subjects from mild and moderate PD patients. Taken together, we have developed/identified an EV blood-based assay that has the potential to be used as a biomarker for PD.

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.

Surgery with or without the addition of radiotherapy is the treatment of choice for canine oral squamous cell carcinoma (SCC). Fractionated radiotherapy alone is also effective in the long-term control of the disease, however coarse fractionated radiotherapy (CF-RT) for gingival SCC has not been extensively reported. The aim of this study was to describe side effects, clinical response, and median survival time (MST) of dogs with gingival SCC treated with CF-RT in the palliative and adjuvant setting. Twenty-one cases from two referral centres in the UK treated with CF-RT for gingival SCC between July 2013 and June 2019 were retrospectively evaluated. Of the 21 dogs, 11 developed mild acute adverse effects. Oral mucositis was the most common radiation induced toxicity. Three dogs developed chronic severe adverse effects (oro-nasal fistula, bone necrosis and gum recession). Overall clinical response rate was 77% in dogs receiving palliative treatment with MST of 365 days (60-1,095 days). MST was not reached for dogs treated in the adjuvant setting with a mean of 466 days (121-730 days). In cases of advanced gross disease CF-RT might have a role in short term palliation of clinical signs. However, it carries a significant risk of late toxicity for cases with unexpectedly long survival times and further investigations are required to identify an optimal CF-RT protocol. Randomized controlled trials are needed to confirm the role of CF-RT as adjuvant treatment of incompletely resected gingival SCC.

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 (

ObjectivesAlterations 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.MethodsIn 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.ResultsWe 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.ConclusionIn 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.

Objectives Serum neurofilament light protein (NfL) is a promising marker of disease onset and progression in Huntington's disease (HD). This study investigated associations between lifestyle factors and NfL levels in HD mutation carriers compared to healthy age‐ and sex‐matched controls. Materials and Methods Participants included 29 HD mutation carriers and 15 healthy controls. Associations between serum NfL concentrations and lifestyle factors, including cardiorespiratory fitness, social network size and diversity, physical activity, cognitive reserve, smoking status, and alcohol consumption, were examined using a stepwise multivariable linear regression model. Results Higher NfL levels were associated with lower cognitive reserve, social network size and diversity and cardiorespiratory fitness in HD mutation carriers. Group × lifestyle factor effects were observed between lower serum NfL levels and a greater social network diversity. Conclusion These findings highlight a relationship between lifestyle factors and NfL levels in HD mutations carriers; however, longitudinal studies are required to confirm if these observed relationships persist over time., Serum neurofilament light protein (NfL) is a promising marker of disease onset and progression in Huntington’s disease; however, it is not yet known how lifestyle factors may impact on NfL levels. Here, we report that lifestyle factors, particularly cognitive reserve, cardiorespiratory fitness and social network size and diversity, are significantly associated with NfL levels.

Huntington’s disease (HD) is a hereditary disorder that typically manifests in adulthood with a combination of motor, cognitive and psychiatric problems. The pathology is caused by a mutation in the huntingtin gene which results in the production of an abnormal protein, mutant huntingtin (mHtt). This protein is ubiquitously expressed and known to confer toxicity to multiple cell types. We have recently reported that HD brains are also characterised by vascular abnormalities, which include changes in blood vessel density/diameter as well as increased blood–brain barrier (BBB) leakage.ObjectivesSeeking to elucidate the origin of these vascular and BBB abnormalities, we studied platelets that are known to play a role in maintaining the integrity of the vasculature and thrombotic pathways linked to this, given they surprisingly contain the highest concentration of mHtt of all blood cells.MethodsWe assessed the functional status of platelets by performing ELISA, western blot and RNA sequencing in a cohort of 71 patients and 68 age- and sex-matched healthy control subjects. We further performed haemostasis and platelet depletion tests in the R6/2 HD mouse model.ResultsOur findings indicate that the platelets in HD are dysfunctional with respect to the release of angiogenic factors and functions including thrombosis, angiogenesis and vascular haemostasis.ConclusionTaken together, our results provide a better understanding for the impact of mHtt on platelet function.

For patients with incurable neurodegenerative disorders such as Huntington's (HD) and Parkinson's disease, cell transplantation has been explored as a potential treatment option. Here, we present the first clinicopathological study of a patient with HD in receipt of cell‐suspension striatal allografts who took part in the NEST‐UK multicenter clinical transplantation trial. Using various immunohistochemical techniques, we found a discrepancy in the survival of grafted projection neurons with respect to grafted interneurons as well as major ongoing inflammatory and immune responses to the grafted tissue with evidence of mutant huntingtin aggregates within the transplant area. Our results indicate that grafts can survive more than a decade post‐transplantation, but show compromised survival with inflammation and mutant protein being observed within the transplant site.

The production and release of extracellular vesicles (EV) is a property shared by all eukaryotic cells and a phenomenon frequently exacerbated in pathological conditions. The protein cargo of EV, their cell type signature and availability in bodily fluids make them particularly appealing as biomarkers. We recently demonstrated that platelets, among all types of blood cells, contain the highest concentrations of the mutant huntingtin protein (mHtt)-the genetic product of Huntington's disease (HD), a neurodegenerative disorder which manifests in adulthood with a complex combination of motor, cognitive and psychiatric deficits. Herein, we used a cohort of 59 HD patients at all stages of the disease, including individuals in pre-manifest stages, and 54 healthy age- and sex-matched controls, to evaluate the potential of EV derived from platelets as a biomarker. We found that platelets of pre-manifest and manifest HD patients do not release more EV even if they are activated. Importantly, mHtt was not found within EV derived from platelets, despite them containing high levels of this protein. Correlation analyses also failed to reveal an association between the number of platelet-derived EV and the age of the patients, the number of CAG repeats, the Unified Huntington Disease Rating Scale total motor score, the Total Functional Capacity score or the Burden of Disease score. Our data would, therefore, suggest that EV derived from platelets with HD is not a valuable biomarker in HD.

Parkinson's disease is typically treated with oral dopamine replacement therapies. However, long-term use is complicated by motor fluctuations from intermittent stimulation of dopamine receptors and off-target effects. ProSavin, a lentiviral vector based gene therapy that delivers local and continuous dopamine, was previously shown to be well tolerated in a Phase I/II first-in-human study, with significant improvements in motor behavior from baseline at 1 year. Here, patients with Parkinson's disease from the open-label trial were followed up in the long term to assess the safety and efficacy of ProSavin after bilateral injection into the putamen. Fifteen patients who were previously treated with ProSavin have been followed for up to 5 years, with some having been seen for 8 years. Eight patients received deep brain stimulation at different time points, and their subsequent assessments continued to assess safety. Ninety-six drug-related adverse events were reported (87 mild, 6 moderate, 3 severe) of which more than half occurred in the first year. The most common drug-related events were dyskinesias (33 events, 11 patients) and on-off phenomena (22 events, 11 patients). A significant improvement in the defined "off" Unified Parkinson's Disease Rating Scale part III motor scores, compared to baseline, was seen at 2 years (mean score 29 · 2 vs. 38 · 4, n = 14, p < 0.05) and at 4 years in 8/15 patients. ProSavin continued to be safe and well tolerated in patients with Parkinson's disease. Moderate improvements in motor behavior over baseline continued to be reported in the majority of patients who could still be evaluated up to 5 years of follow-up.

Literature describing medical treatment of canine prostatic carcinoma (PC) is sparse. The aims of this study were to assess outcomes, including time to progression (TTP) and median survival time (MST), of canine PC treated with non-steroidal anti-inflammatory drugs (NSAIDs) and/or chemotherapy, and to identify prognostic factors. Records from 8 institutions were searched for dogs with cytologically or histologically confirmed PC without bladder involvement: 67 dogs were included. Presenting signs were urinary (25), gastrointestinal ([GI], 11) and systemic (3); 16 dogs had GI and urinary signs, 7 dogs had systemic signs with concurrent GI or urinary signs and in 5 dogs the tumour was an incidental finding. Out of 27 dogs, 9 (33%) had positive urine culture. Metastases were identified in 26 dogs to lymph nodes (19), lungs (10), bone (2) and liver (1). Treatment included NSAIDs and chemotherapy (32), NSAIDs alone (31) and chemotherapy alone (4). The overall MST was 82 days (range 9-752) and median TTP was 63 days (range 9-752). Dogs receiving NSAIDs combined with chemotherapy experienced a significantly longer MST (106 vs 51 days; P = .035) and TTP (76 vs 44 days; P = .02) compared to dogs receiving NSAIDs alone. Intact dogs and those with metastatic disease had significantly shorter MST (31 vs 90 days, P = .018 and 49 vs 109 days, P = .037, respectively); intact dogs also had significantly shorter TTP (25 vs 63 days, P = .0003). This study suggests that a combination of NSAIDs and chemotherapy may improve outcomes in canine PC. Metastatic disease and being entire negatively influenced prognosis.

Preclinical data have shown that rilmenidine can regulate autophagy in models of Huntington’s disease (HD), providing a potential route to alter the disease course in patients. Consequently, a 2-year open-label study examining the tolerability and feasibility of rilmenidine in mild-moderate HD was undertaken. 18 non-demented patients with mild to moderate HD took daily doses of 1 mg Rilmenidine for 6 months and 2 mg for a further 18 months followed by a 3-month washout period. The primary outcome was the number of withdrawals and serious adverse events. Secondary outcomes included safety parameters and changes in disease-specific variables, such as motor, cognitive and functional performance, structural MRI and serum metabolomic analysis. 12 patients completed the study; reasons for withdrawal included problems tolerating study procedures (MRI, and venepuncture), depression requiring hospital admission and logistical reasons. Three serious adverse events were recorded, including hospitalisation for depression, but none were thought to be drug-related. Changes in secondary outcomes were analysed as the annual rate of change in the study group. The overall change was comparable to changes seen in recent large observational studies in HD patients, though direct statistical comparisons to these studies were not made. Chronic oral administration of rilmenidine is feasible and well-tolerated and future, larger, placebo-controlled, studies in HD are warranted. Trial registration: EudraCT number 2009-018119-14. Electronic supplementary material The online version of this article (doi:10.1007/s00415-017-8647-0) contains supplementary material, which is available to authorized users.

Huntington's disease is an inherited fatal progressive neurodegenerative disorder. A possible new Raman ‘spectral’ biomarker was identified that uses a tiny drop of patients' blood serum; thus can have immense diagnostic and therapeutic implications., Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an abnormal CAG expansion in exon 1 of the huntingtin (HTT) gene. Given its genetic basis it is possible to study patients both in the pre-manifest and manifest stages of the condition. While disease onset can be modelled using CAG repeat size, there are no easily accessible biomarkers that can objectively track disease progression. Here, we employed a holistic approach using spectral profiles generated using both surface-enhanced Raman spectroscopy (SERS) and Raman Spectroscopy (RS), on the serum of healthy participants and HD patients covering a wide spectrum of disease stages. We found that there was both genotype- and gender-specific segregation on using the full range in the fingerprint region with both SERS and RS. On a more detailed interrogation using specific spectral intervals, SERS revealed significant correlations with disease progression, in particular progression from pre-manifest through to advanced HD was associated with serum molecules related to protein misfolding and nucleotide catabolism. Thus, this study shows the potential of Raman spectroscopy-based techniques for stratification of patients and, of SERS, in particular, to track disease status through provision of ‘spectral’ biomarkers in HD, with clinical applications for other diseases and trials looking at disease modifying therapies.

A seven year old male neutered Labrador weighing 35kg with a two weekhistory of left forelimb lameness was diagnosed with osteosarcoma of thethird metacarpal bone. No pulmonary metastases were detected and rayamputation (removal of the left third metacarpal bone and 3rd phalanx enbloc)was performed. Circumferential sutures were placed aroundmetacarpals 2 and 4 to realign the adjacent bones and digits during thehealing period. The dog received 6 cycles of single agent carboplatin(300mg/m2) postoperatively. Restaging 9 months postoperatively revealedno evidence of metastasis or recurrence. Two years postoperatively, thedog has no evidence of complications or lameness. Thoracic limbamputation and postoperative adjunctive therapy are considered the goldstandard treatment for appendicular osteosarcoma; however, anoncological compartment excision of the this bone tumour was performedwith similar outcome for the patient whilst preserving the limb.

Antonio Giuliano and colleagues argue that 'anticancer' supplements could be harmful and hinder chemotherapy and radiotherapy treatment, and so their use should be discouraged in cancer patients.

Background Huntington9s disease (HD) is an autosomal dominant neurodegenerative disorder characterised by a triad of motor, psychiatric and cognitive deficits with the latter classically attributed to disruption of frontostriatal networks. However, emerging evidence from animal models of HD suggests that some of the early cognitive deficits may have a hippocampal basis. The objective of this study was to link previous rodent findings in this area to clinical practice. Methods In this study, 94 participants included patients with early HD, premanifest HD and age-matched controls underwent hippocampal-based cognitive assessments. These included a virtual reality version of the Morris water maze, a task involved participants having to swim through a virtual pool to find a submerged platform using a joystick, and the Cambridge Neuropsychological Test Automated Battery (CANTAB) paired associates learning task, a test also known to rely on hippocampal integrity. Results Patients with early HD showed impaired performance in both the virtual Morris water maze and the CANTAB paired associates learning. Such deficits were also correlated with estimated years to diagnosis in premanifest participants. Conclusions This study highlights the merit of using analogous tests in the laboratory and clinic and demonstrates that hippocampal impairments are an early feature of HD in patients as previously shown in rodent models of the disease. As such, they could be used not only to assist in the diagnosis of disease onset, but may also be useful as an outcome measure in future therapeutic trials.

Background Despite its monogenic cause, the cognitive problems in Huntington’s Disease are heterogeneous. This is particularly pronounced in the premanifest (preHD) stage of the disease. The existing tools cannot explain all of the heterogeneity observed nor can they accurately inform the progression of these aspects of the disease at an individual level. Method We have developed a data driven mathematical model using the cross-sectional data from the first ENROLL-HD data cut to classify preHD participants into two groups. Machine learning methods were used to identify variables of interest that were inputted into a support vector machine which was used to classify participants. The model was validated in a local subset of the PREDICT-HD cohort. Results The support vector machine used performance on four cognitive tests to classify participants into two distinct groups: group one who perform worse on cognitive measures and group two who perform better. Importantly, the two groups did not differ on measure of age, CAG repeat number and disease burden measures. We also found a significant genetic association between membership of the cognitively better group and the minor alleles of NCOR1 and ADORA2B through supplementary genotyping analysis. Conclusion This work suggests that participants can be classified into distinct groups on the basis of their cognitive performance alone, even in the premanifest stage of HD. There may be genetic interactions within the HD gene pathway that explain some of the cognitive heterogeneity that we see in preHD patients.

Whilst the diagnosis of Huntington’s disease (HD) is reliant on the presence of motor disturbances, progressive cognitive impairments can precede overt motor features by up to 15 years (Paulsen, 2011) and often place the greatest burden on both HD patients and their families (Brandt and Butters, 1986). It has been hypothesised that there is an increase in DA transmission in early stages of HD as drugs that block DA receptors help alleviate the chorea (Cepeda, 2015). However, despite knowing that DA is critical for cognition in a healthy population, little is understood about the consequences of these early changes on cognition in HD. Importantly, it is not known this process if influenced by the DA antagonists used to treat motor features of HD. In this study we use the dataset from Enroll-HD, the world’s largest observational study for Huntington’s disease families, to assess the effects of dopamine antagonist medication on cognitive decline. Participants were grouped into those taking dopamine antagonist medication during the assessment period and a control group who were not taking DA medication but were matched for age, gender and disease stage using propensity score matching. Results showed that participants taking DA antagonists had a significantly greater annual decline in performance on the enrol cognitive task battery than those who were not on DA medication. Furthermore, a group of participants who came off dopamine antagonists during the assessment period did not differ from the control group in rate of cognitive decline during the period they were off the medication. Together these results suggest that dopamine antagonist medication may be detrimental to cognition, which has important implications for the clinical management of cognitive symptoms.

Background Cognitive processing speed has been found to be slower in those with manifest and premanifest Huntington’s disease (Maroof, Gross & Brandt, 2011) compared to controls. However, the most commonly employed measures of cognitive processing speed, such as the Stroop Test, Symbol Digit Modalities Test and Trail Making, all rely on motor responses, either written or verbal. Given that motor deficits are a feature of HD, even during the premanifest stage (Biglan, et al., 2009), it is important to understand whether poor performance on these tests are purely due to cognitive processing speed issues, or if they are confounded by motor response speed. This is particularly interesting in premanifest HD, as these patients do not have motor problems that would lead to a clinical diagnosis of manifest disease, but may have slowed motor responses (Tabrizi, et al., 2013). Aims The aim of this study is to explore how much of the variance in traditional cognitive processing tasks can be accounted for by motor speed in HD participants. Methods This is a retrospective study using data from cognitive processing speed tasks collected as part of the Enroll HD study at the Cambridge Site; including the Stroop Test, Symbol Digit Modalities Task and Trail Making, combined with data from a simple speeded hand tapping task carried out as part of participants routine clinic visit, which provides a marker of motor speed. Statistical analysis was used to explore the relationship between performance on cognitive processing tasks and tapping speed at different stages of disease with particular emphasis on patients either side of the clinical diagnosis. Conclusions Understanding the contribution of motor speed to participants’ scores on measures of cognitive processing speed provides a more in depth understanding of why people with HD experience a worsening of performance and impacts the way in which data on these tasks is interpreted. References . Biglan, K. M., Ross, C. A., Langbehn, D. R., Aylward, E. H., Stout, J. C., Queller, S., Paulsen, J. S. (2009). Motor abnormalities in premanifest persons with Huntington’s disease: The PREDICT-HD study. Movement Disorders, 2412, 1763–1772. doi:10.1002/mds.22601 . Maroof, D. A., Gross, A. L., & Brandt, J. (2011). Modeling longitudinal change in motor and cognitive processing speed in presymptomatic Huntington’s disease. Journal of Clinical and Experimental Neuropsychology, 338, 901–909. doi:10.1080/13803395.2011.574606 . Tabrizi, S. J., Scahill, R. I., Owen, G. N., Durr, A., Leavitt, B. R., Roos, R. A. C., Langbehn, D. R. (2013). Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington’s disease in the TRACK-HD study: analysis of 36-month observational data. Lancet Neurology, 127, 637–649. DOI: 10.1016/S1474-4422(13)70088-7