What we don't need to prove but need to do in multidisciplinary treatment and care in Huntington's disease: a position paper.

BACKGROUND: Huntington's disease is a complex neurodegenerative hereditary disease with symptoms in all domains of a person's functioning. It begins after a healthy start in life and leads through the relentless progression over many years to complete care dependency and finally death. To date, the disease is incurable. The long progressive complex nature of the disease demands multiple disciplines for treatment and care of patient and family. These health care providers need inter- and multidisciplinary collaboration to persevere and be efficacious in this devastating disease trajectory. DISCUSSION: The position paper outlines current knowledge and experience alongside the experience and consensus of a recognised group of HD multidisciplinary experts. Additionally the patient's voice is clear and calls for health care providers with a holistic view on patient and family. Building long-term trust is a cornerstone of the network around the patient. This paper describes a managed care network comprising all the needed professionals and services. In the health care system, the role of a central coordinator or case manager is of key importance but lacks an appropriate guideline. Other disciplines currently without guidelines are general practitioners, nurses, psychologists, and social workers. Guidelines for neurologists, psychiatrists, geneticists, occupational therapists, speech and language therapists, physiotherapists, dieticians, and dentists are being discussed. Apart from all these profession-specific guidelines, distinctive inter- and multidisciplinary collaboration requirements must be met. CONCLUSIONS AND RECOMMENDATIONS: The complex nature of Huntington's disease demands multidisciplinary treatment and care endorsed by international regulations and the lay association. Available guidelines as reviewed in this paper should be used, made available by a central body, and updated every 3-5 years. Time needs to be invested in developing missing guidelines but the lack of this 'proof' should not prevent the 'doing' of good care.

Environmental stimulation in Huntington disease patients and animal models.

While Huntington disease (HD) is caused solely by a polyglutamine expansion in the huntingtin gene, environmental factors can influence HD onset and progression. Here, we review studies linking environment and HD in both humans and animal models. In HD patients, we find that: (i) an active lifestyle associates with both a delayed age at onset of HD and a decreased severity of symptoms, (ii) applying physical exercise and behavioral therapies in small cohorts of HD subjects indicate promising effects on the HD symptomatology, (iii) Mediterranean diet correlates with lower motor impairment, and treatments based on omega-3 fatty acids improve motor function , whereas (iv) increased cortisol levels associate with specific HD symptoms. In animal models, in line with the evidence in humans, physical exercise, environmental enrichment and different types of dietary intervention ameliorate or delay several HD phenotypes. In contrast, stress appears to be involved in the HD pathogenesis, and HD mice present increased stress sensitivity. Importantly, studies in animal models have uncovered several molecular factors mediating environmental effects on HD associated neuropathology. However, the influence of the environment on several key HD mechanisms as well as the underlying regulatory factors remain to be explored. Given the role of epigenetic factors and modifications in the interplay between environment and genes, the exploration of their role as mechanisms underlying the environmental action in HD is a promising avenue for both our fundamental understanding of the disease and as a potential for therapy.

Label-free photothermal disruption of cytotoxic aggregates rescues pathology in a C. elegans model of Huntington's disease.

Aggregation of proteins is a prominent hallmark of virtually all neurodegenerative disorders including Alzheimer's, Parkinson's and Huntington's diseases. Little progress has been made in their treatment to slow or prevent the formation of aggregates by post-translational modification and regulation of cellular responses to misfolded proteins. Here, we introduce a label-free, laser-based photothermal treatment of polyglutamine (polyQ) aggregates in a C. elegans nematode model of huntingtin-like polyQ aggregation. As a proof of principle, we demonstrated that nanosecond laser pulse-induced local photothermal heating can directly disrupt the aggregates so as to delay their accumulation, maintain motility, and extend the lifespan of treated nematodes. These beneficial effects were validated by confocal photothermal, fluorescence, and video imaging. The results obtained demonstrate that our theranostics platform, integrating photothermal therapy without drugs or other chemicals, combined with advanced imaging to monitor photothermal ablation of aggregates, initiates systemic recovery and thus validates the concept of aggregate-disruption treatments for neurodegenerative diseases in humans.

CPEB alteration and aberrant transcriptome-polyadenylation lead to a treatable SLC19A3 deficiency in Huntington's disease.

Huntington's disease (HD) is a hereditary neurodegenerative disorder of the basal ganglia for which disease-modifying treatments are not yet available. Although gene-silencing therapies are currently being tested, further molecular mechanisms must be explored to identify druggable targets for HD. Cytoplasmic polyadenylation element binding proteins 1 to 4 (CPEB1 to CPEB4) are RNA binding proteins that repress or activate translation of CPE-containing transcripts by shortening or elongating their poly(A) tail. Here, we found increased CPEB1 and decreased CPEB4 protein in the striatum of patients and mouse models with HD. This correlated with a reprogramming of polyadenylation in 17.3% of the transcriptome, markedly affecting neurodegeneration-associated genes including PSEN1, MAPT, SNCA, LRRK2, PINK1, DJ1, SOD1, TARDBP, FUS, and HTT and suggesting a new molecular mechanism in neurodegenerative disease etiology. We found decreased protein content of top deadenylated transcripts, including striatal atrophy­linked genes not previously related to HD, such as KTN1 and the easily druggable SLC19A3 (the ThTr2 thiamine transporter). Mutations in SLC19A3 cause biotin-thiamine­responsive basal ganglia disease (BTBGD), a striatal disorder that can be treated with a combination of biotin and thiamine. Similar to patients with BTBGD, patients with HD demonstrated decreased thiamine in the cerebrospinal fluid. Furthermore, patients and mice with HD showed decreased striatal concentrations of thiamine pyrophosphate (TPP), the metabolically active form of thiamine. High-dose biotin and thiamine treatment prevented TPP deficiency in HD mice and attenuated the radiological, neuropathological, and motor HD-like phenotypes, revealing an easily implementable therapy that might benefit patients with HD.

An Australian Neuro-Palliative perspective on Huntington's disease: a case report.

BACKGROUND: Huntington's Disease (HD) is an incurable, progressive neuro-degenerative disease. For patients with HD access to palliative care services is limited, with dedicated Neuro-Palliative Care Services rare in Australia. We discuss the experiences of and benefits to a patient with late-stage HD admitted to our Neuro-Palliative Care service. CASE PRESENTATION: We present the case of a patient with a 16-year history of HD from time of initial genetic testing to admission to our Neuro-Palliative Care service with late-stage disease. CONCLUSIONS: Given the prolonged, fluctuating and heterogenous HD trajectory, measures need to be implemented to improve earlier access to multi-specialty integrative palliative care services. Given the good outcomes of our case, we strongly advocate for the role of specialised Neuro-Palliative Care services to bridge the gap between clinical need and accessibility.

Experiences of Mindfulness-Based Cognitive Therapy for Premanifest Huntington's Disease.

BACKGROUND: Psychological difficulties such as anxiety, depression, and irritability are common in Huntington's disease, even for premanifest individuals. However, very little evidence exists of psychological approaches to manage this distress. We have conducted a feasibility study with an embedded qualitative component to investigate the possibility of using mindfulness-based cognitive therapy (MBCT) and present here the findings from the qualitative data. OBJECTIVE: To investigate the experience of premanifest individuals learning and practising mindfulness through completing a course of MBCT. METHODS: Twelve premanifest individuals completed a course of MBCT and attended three follow up reunion meetings over the following year. Eleven participants agreed to be interviewed post-course and ten participants one year post-course about their experience of the course and any impact on their lives. Seven participants nominated a friend or relative (supporter) to be involved in the research, of whom six agreed to be interviewed post-course and two at one year about the impact of the course on the participants. Data were analysed using reflexive thematic analysis. RESULTS: Four themes were constructed from the data: 1) A meeting of minds: the group facilitating learning and support; 2) Mindfulness is hard, but enables more effective emotional management; 3) Mindfulness can change the relationship with self and others; and 4) Benefiting from mindfulness: the importance of persistence. CONCLUSION: The participants who completed the course found it beneficial. Some participants reported reductions in psychological distress, a greater sense of calm and better emotion regulation, with some of these positive changes also noticed by supporters. MBCT is worthy of further investigation for this population.

A Review of the Clinical Evidence for Complementary and Alternative Medicine in Huntington's Disease.

Background: There is a lack of published guidelines related to the use of complementary and alternative medicine (CAM) for Huntington's disease (HD). We conducted a review of the literature to summarize the available evidence for various mind-body practices and nutraceuticals. Methods: PubMed and Cochrane Library electronic databases were searched independently from inception to February 2019 by two independent raters. Studies were classified for the level of evidence (Class I, II, III, or IV) according to the American Academy of Neurology (AAN) classification scale. Results: Randomized controlled trials in HD were reviewed for mind-body interventions (dance therapy, music therapy, and exercise), alternative systems (traditional Chinese medicine [TCM]), and nutraceuticals/diet (aminooxyacetic acid [AOAA], coenzyme q10, creatine, cannabinoids, alpha-tocopherol, eicosapentaenoic acid, idebenone, levocarnitine, and triheptanoin). Few studies met AAN Class I or II level of evidence for benefits, and these are highlighted. Discussion: There is a relative paucity of clinical trials examining CAM modalities in HD when compared to other neurodegenerative disorders. Currently, there is no evidence supporting disease modification or symptom improvement with any specific dietary or nutraceutical supplement for HD. Supervised exercise and contemporary dance are safe for people with HD, but more robust studies are warranted to guide specific recommendations for these and other mind-body interventions.

Therapeutic Use of Music, Dance, and Rhythmic Auditory Cueing for Patients with Huntington's Disease: A Systematic Review.

BACKGROUND: Studies have assessed the therapeutic effect of music, dance, and rhythmic auditory cueing for patients with Huntington's disease (HD). However, the synthesis of evidence in support of their positive impact on symptoms is lacking. OBJECTIVE: We conducted a systematic literature review to evaluate the potential benefits of music, dance, and rhythm on the cognitive, psychiatric and motor function in patients with HD. METHODS: Two- and three-keyword searches and a manual search identified medical literature published from 1999 through 2019. We considered literature that assessed outcomes of art-based rehabilitation programs or individual modalities for persons with early, middle, or advanced HD. Structured analysis was conducted using data entry tables with categories for patient health status, art methods, and outcomes. RESULTS: Seven articles and six abstracts met eligibility criteria, of which nine evaluated art-based rehabilitation programs. Studies mainly assessed cognitive, psychiatric, and motor functions through music, dance, or rhythm modalities. Although results were conflicting, in summary improvements to motor function were dependent on disease severity and more responsive to art therapy programs than rhythm-motor synchronization. Benefits to global cognition that resulted from rhythmic training correlated with microstructural changes. Qualitative data verified a positive impact on language production, chorea, behavior, and quality of life. CONCLUSIONS: Our review has shown a potential benefit of music, dance, and rhythm for patients with HD, which is particularly important for a disease that has no cure. Art forms seemed to affect cognitive, psychiatric, motor, psychosocial, and neuroanatomical domains. However, evidence is preliminary, warranting further investigation to establish the foundation for this field.

Murine Models of Huntington's Disease for Evaluating Therapeutics.

Huntington's disease (HD) is an autosomal dominant progressive neurological disorder characterized by motor, cognitive, and psychiatric symptoms that typically present later on in life, although juvenile cases do exist. The identification of the disease-causing mutation, a CAG triplet repeat expansion in the HTT gene, in 1993 generated numerous investigations into the cellular and molecular pathways underlying the disorder. HD mouse models have played a prominent role in these studies, and the use of these mouse models of HD in the development and evaluation of novel therapeutic strategies is reviewed in this chapter. As new interventions and therapeutic approaches are evaluated and implemented, genetic mouse models will continue to be used with the hope of developing effective treatments for HD.

Translating Antisense Technology into a Treatment for Huntington's Disease.

Advances in molecular biology and genetics have been used to elucidate the fundamental genetic mechanisms underlying central nervous system (CNS) diseases, yet disease-modifying therapies are currently unavailable for most CNS conditions. Antisense oligonucleotides (ASOs) are synthetic single stranded chains of nucleic acids that bind to a specific sequence on ribonucleic acid (RNA) and regulate posttranscriptional gene expression. Decreased gene expression with ASOs might be able to reduce production of the disease-causing protein underlying dominantly inherited neurodegenerative disorders. Huntington's disease (HD), which is caused by a CAG repeat expansion in exon 1 of the huntingtin (HTT) gene and leads to the pathogenic expansion of a polyglutamine (PolyQ ) tract in the N terminus of the huntingtin protein (Htt), is a prime candidate for ASO therapy.State-of-the art translational science techniques can be applied to the development of an ASO targeting HTT RNA, allowing for a data-driven, stepwise progression through the drug development process. A deep and wide-ranging understanding of the basic, preclinical, clinical, and epidemiologic components of drug development will improve the likelihood of success. This includes characterizing the natural history of the disease, including evolution of biomarkers indexing the underlying pathology; using predictive preclinical models to assess the putative gain-of-function of mutant Htt protein and any loss-of-function of the wild-type protein; characterizing toxicokinetic and pharmacodynamic effects of ASOs in predictive animal models; developing sensitive and reliable biomarkers to monitor target engagement and effects on pathology that translate from animal models to patients with HD; establishing a drug delivery method that ensures reliable distribution to relevant CNS tissue; and designing clinical trials that move expeditiously from proof of concept to proof of efficacy. This review focuses on the translational science techniques that allow for efficient and informed development of an ASO for the treatment of HD.

Huntington's disease: Current and future therapeutic prospects.

Huntington's disease is a progressive neurodegenerative disorder for which therapies are woefully inadequate and do not prevent inevitable progression. Currently approved therapies are primarily aimed at treating chorea, but do not address the more clinically meaningful motor, behavioral, and cognitive features of the disease. However, there are a number of promising new therapies that are currently being studied in the laboratory, and in the clinic. This article will review the wide variety of therapies currently being tested, the advances in clinical trials and end points, and the many potentially relevant new targets. © 2018 International Parkinson and Movement Disorder Society.

Huntington's Disease Outpatient Clinic for Functional Diagnosis and Treatment: Coming to Consensus: How Long Term Care Facility Procedures Complement Specialist Diagnosis and Treatment.

Huntington's disease (HD) patients and families deserve expert treatment and care throughout their lives, but uniformity in functional diagnosis and treatment was lacking. In the aim of reaching this uniformity on day-to-day treatment and care offered by multidisciplinary outreach teams from Dutch long term care facilities for ambulatory HD patients, a consensus trajectory was started to harmonise our care programme with international standards and within the country. The consensus statements, given as supplementary material, should lead to expert treatment and care for HD families throughout the Netherlands and this manuscript should contribute and revitalise a global discussion on standards of treatment and care.

Understandings of psychological difficulties in people with the Huntington's disease gene and their expectations of psychological therapy.

OBJECTIVES: This study sought to investigate how people who had tested positive for the Huntington's disease (HD) gene mutation understood and experienced psychological distress and their expectations of psychological therapy. DESIGN: A qualitative methodology was adopted involving semi-structured interviews and interpretative phenomenological analysis (IPA). METHOD: A total of nine participants (five women and four men) who had opted to engage in psychological therapy were recruited and interviewed prior to the start of this particular psychological therapeutic intervention. Interviews were transcribed verbatim and analysed using IPA whereby themes were analysed within and across transcripts and classified into superordinate themes. RESULTS: Three superordinate themes were developed: Attributing psychological distress to HD: 'you're blaming everything on that now'; Changes in attributions of distress over time: 'in the past you'd just get on with it'; and Approaching therapy with an open mind, commitment, and hope: 'a light at the end of the tunnel'. CONCLUSION: Understandings of psychological distress in HD included biological and psychological explanations, with both often being accepted simultaneously by the same individual but with biomedical accounts generally dominating. Individual experience seemed to reflect a dynamic process whereby people's understanding and experience of their distress changed over time. Psychological therapy was accepted as a positive alternative to medication, providing people with HD with hope that their psychological well-being could be enhanced. PRACTITIONER POINTS: People with the Huntington's disease gene mutation have largely biomedical understandings of their psychological distress. This largely biomedical understanding does not, however, preclude them for being interested in the potential gains resulting from psychological therapy. The mechanisms of psychological therapy should be explained in detail before therapy and explored along with current attributions of distress.

Therapies targeting DNA and RNA in Huntington's disease.

No disease-slowing treatment exists for Huntington's disease, but its monogenic inheritance makes it an appealing candidate for the development of therapies targeting processes close to its genetic cause. Huntington's disease is caused by CAG repeat expansions in the HTT gene, which encodes the huntingtin protein; development of therapies to target HTT transcription and the translation of its mRNA is therefore an area of intense investigation. Huntingtin-lowering strategies include antisense oligonucleotides and RNA interference targeting mRNA, and zinc finger transcriptional repressors and CRISPR-Cas9 methods aiming to reduce transcription by targeting DNA. An intrathecally delivered antisense oligonucleotide that aims to lower huntingtin is now well into its first human clinical trial, with other antisense oligonucleotides expected to enter trials in the next 1-2 years and virally delivered RNA interference and zinc finger transcriptional repressors in advanced testing in animal models. Recent advances in the design and delivery of therapies to target HTT RNA and DNA are expected to improve their efficacy, safety, tolerability, and duration of effect in future studies.

The Effect of Music Therapy in Patients with Huntington's Disease: A Randomized Controlled Trial.

BACKGROUND: Music therapy may have beneficial effects on improving communication and expressive skills in patients with Huntington's disease (HD). Most studies are, however, small observational studies and methodologically limited. Therefore we conducted a multi-center randomized controlled trial. OBJECTIVE: To determine the efficacy of music therapy in comparison with recreational therapy in improving quality of life of patients with advanced Huntington's disease by means of improving communication. METHOD: Sixty-three HD-patients with a Total Functional Capacity (TFC) score of ≤7, admitted to four long-term care facilities in The Netherlands, were randomized to receive either group music therapy or group recreational therapy in 16 weekly sessions. They were assessed at baseline, after 8, 16 and 28 weeks using the Behaviour Observation Scale for Huntington (BOSH) and the Problem Behaviour Assessment-short version (PBA-s). A linear mixed model with repeated measures was used to compare the scores between the two groups. RESULTS: Group music therapy offered once weekly for 16 weeks to patients with Huntington's disease had no additional beneficial effect on communication or behavior compared to group recreational therapy. CONCLUSION: This was the first study to assess the effect of group music therapy on HD patients in the advanced stages of the disease. The beneficial effects of music therapy, recorded in many, mainly qualitative case reports and studies, could not be confirmed with the design (i.e. group therapy vs individual therapy) and outcome measures that have been used in the present study. A comprehensive process-evaluation alongside the present effect evaluation is therefore performed.

The expanded CAG repeat in the huntingtin gene as target for therapeutic RNA modulation throughout the HD mouse brain.

The aim of these studies was to demonstrate the therapeutic capacity of an antisense oligonucleotide with the sequence (CUG)7 targeting the expanded CAG repeat in huntingtin (HTT) mRNA in vivo in the R6/2 N-terminal fragment and Q175 knock-in Huntington's disease (HD) mouse models. In a first study, R6/2 mice received six weekly intracerebroventricular infusions with a low and high dose of (CUG)7 and were sacrificed 2 weeks later. A 15-60% reduction of both soluble and aggregated mutant HTT protein was observed in striatum, hippocampus and cortex of (CUG)7-treated mice. This correction at the molecular level resulted in an improvement of performance in multiple motor tasks, increased whole brain and cortical volume, reduced levels of the gliosis marker myo-inositol, increased levels of the neuronal integrity marker N-aceyl aspartate and increased mRNA levels of the striatal marker Darpp-32. These neuroanatomical and neurochemical changes, together with the improved motor performance, suggest that treatment with (CUG)7 ameliorates basal ganglia dysfunction. The HTT-lowering was confirmed by an independent study in Q175 mice using a similar (CUG)7 AON dosing regimen, further demonstrating a lasting reduction of mutant HTT protein in striatum, hippocampus and cortex for up to 18 weeks post last infusion along with an increase in motor activity. Based on these encouraging results, (CUG)7 may thus offer an interesting alternative HTT-lowering strategy for HD.

Development of the Music Therapy Assessment Tool for Advanced Huntington's Disease: A Pilot Validation Study.

BACKGROUND: Case studies of people with Huntington's disease (HD) report that music therapy provides a range of benefits that may improve quality of life; however, no robust music therapy assessment tools exist for this population. OBJECTIVE: Develop and conduct preliminary psychometric testing of a music therapy assessment tool for patients with advanced HD. METHODS: First, we established content and face validity of the Music Therapy Assessment Tool for Advanced HD (MATA-HD) through focus groups and field testing. Second, we examined psychometric properties of the resulting MATA-HD in terms of its construct validity, internal consistency, and inter-rater and intra-rater reliability over 10 group music therapy sessions with 19 patients. RESULTS: The resulting MATA-HD included a total of 15 items across six subscales (Arousal/Attention, Physical Presentation, Communication, Musical, Cognition, and Psychological/Behavioral). We found good construct validity (r ≥ 0.7) for Mood, Communication Level, Communication Effectiveness, Choice, Social Behavior, Arousal, and Attention items. Cronbach's α of 0.825 indicated good internal consistency across 11 items with a common focus of engagement in therapy. The inter-rater reliability (IRR) Intra-Class Coefficient (ICC) scores averaged 0.65, and a mean intra-rater ICC reliability of 0.68 was obtained. Further training and retesting provided a mean of IRR ICC of 0.7. CONCLUSION: Preliminary data indicate that the MATA-HD is a promising tool for measuring patient responses to music therapy interventions across psychological, physical, social, and communication domains of functioning in patients with advanced HD.

Music therapy in Huntington's disease: a protocol for a multi-center randomized controlled trial.

BACKGROUND: Huntington's disease is a progressive, neurodegenerative disease with autosomal dominant inheritance, characterized by motor disturbances, cognitive decline and behavioral and psychological symptoms. Since there is no cure, all treatment is aimed at improving quality of life. Music therapy is a non-pharmacological intervention, aiming to improve the quality of life, but its use and efficacy in patients with Huntington's disease has hardly been studied. In this article, a protocol is described to study the effects of music therapy in comparison with a control intervention to improve quality of life through stimulating expressive and communicative skills. By targeting these skills we assume that the social-cognitive functioning will improve, leading to a reduction in behavioral problems, resulting in an overall improvement of the quality of life in patients with Huntington's disease. METHODS/DESIGN: The study is designed as a multi-center single-blind randomised controlled intervention trial. Sixty patients will be randomised using centre-stratified block-permuted randomisation. Patients will be recruited from four long-term care facilities specialized in Huntington's disease-care in The Netherlands. The outcome measure to assess changes in expressive and communication skills is the Behaviour Observation Scale Huntington and changes in behavior will be assessed by the Problem Behaviour Assesment-short version and by the BOSH. Measurements take place at baseline, then 8, 16 (end of intervention) and 12 weeks after the last intervention (follow-up). DISCUSSION: This randomized controlled study will provide greater insight into the effectiveness of music therapy on activities of daily living, social-cognitive functioning and behavior problems by improving expressive and communication skills, thus leading to a better quality of life for patients with Huntington's disease. TRIAL REGISTRATION: Netherlands Trial Register: NTR4904 , registration date Nov. 15, 2014.

Therapeutic strategies for circadian rhythm and sleep disturbances in Huntington disease.

Aside from the well-known motor, cognitive and psychiatric signs and symptoms, Huntington disease (HD) is also frequently complicated by circadian rhythm and sleep disturbances. Despite the observation that these disturbances often precede motor onset and have a high prevalence, no studies are available in HD patients which assess potential treatments. In this review, we will briefly outline the nature of circadian rhythm and sleep disturbances in HD and subsequently focus on potential treatments based on findings in other neurodegenerative diseases with similarities to HD, such as Parkinson and Alzheimer disease. The most promising treatment options to date for circadian rhythm and sleep disruption in HD include melatonin (agonists) and bright light therapy, although further corroboration in clinical trials is warranted.