Journal of Huntington's Disease - Volume 8, issue 4

Authors: Cheong, Rachel Y. | Gabery, Sanaz | Petersén, Åsa

Article Type: Review Article

Abstract:  Huntington’s disease (HD) is a fatal genetic neurodegenerative disorder. It has mainly been considered a movement disorder with cognitive symptoms and these features have been associated with pathology of the striatum and cerebral cortex. Importantly, individuals with the mutant huntingtin gene suffer from a spectrum of non-motor features often decades before the motor disorder manifests. These symptoms and signs include a range of psychiatric symptoms, sleep problems and metabolic changes with weight loss particularly in later stages. A higher body mass index at diagnosis is associated with slower disease progression. The common psychiatric symptom of apathy progresses with the disease. …The fact that non-motor features are present early in the disease and that they show an association to disease progression suggest that unravelling the underlying neurobiological mechanisms may uncover novel targets for early disease intervention and better symptomatic treatment. The hypothalamus and the limbic system are important brain regions that regulate emotion, social cognition, sleep and metabolism. A number of studies using neuroimaging, postmortem human tissue and genetic manipulation in animal models of the disease has collectively shown that the hypothalamus and the limbic system are affected in HD. These findings include the loss of neuropeptide-expressing neurons such as orexin (hypocretin), oxytocin, vasopressin, somatostatin and VIP, and increased levels of SIRT1 in distinct nuclei of the hypothalamus. This review provides a summary of the results obtained so far and highlights the potential importance of these changes for the understanding of non-motor features in HD. Show more

Keywords: Huntington’s disease, hypothalamus, orexin, hypocretin, oxytocin, vasopressin

DOI: 10.3233/JHD-190372

Citation: Journal of Huntington's Disease, vol. 8, no. 4, pp. 375-391, 2019

Authors: Schwartz, Anna E. | van Walsem, Marleen R. | Brean, Are | Frich, Jan C.

Article Type: Review Article

Abstract: 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. Show more

Keywords: Music therapy, dance therapy, art therapy, Huntington’s disease

DOI: 10.3233/JHD-190370

Citation: Journal of Huntington's Disease, vol. 8, no. 4, pp. 393-420, 2019

Authors: Cotter, Kristina | Siskind, Carly E. | Sha, Sharon J. | Hanson-Kahn, Andrea K.

Article Type: Research Article

Abstract: Background: New therapies that could modify the disease course of Huntington’s disease (HD) are entering clinical trials. However, conceptions about clinical research from the HD community are unknown. This knowledge could help inform patient-clinician discussions surrounding clinical trial participation. Objective: The purpose of this study was to assess clinical trial attitudes and understanding in the HD community. Methods: We developed a survey incorporating two measures of trial understanding and attitudes and the impact of therapeutic route of administration on hypothetical trial participation. The survey was distributed via emails, flyers, and social media through HD-related organizations. …Results: There were 73 responses. Individuals self-reported as clinically diagnosed with HD, gene positive but asymptomatic, or primary caregivers. Respondents viewed clinical trials positively and generally viewed trials as safe. Individuals with prior HD-related research experience were less likely to have negative expectations about trials than those without research experience (p  = 0.002), and women had higher information needs than men (p  = 0.001). Individuals with HD were more likely than the other groups to experience therapeutic misconception (p  = 0.002). All respondents were able to appraise risks and benefits of research but exhibited optimism about trial outcomes. Willingness to participate was highest when the route of administration was minimally invasive. Conclusions: While the HD community views clinical trials positively, patients with HD are at high risk for therapeutic misconception and all groups are optimistic about trial outcomes. Limitations of this study include a small sample that may be inclined to view research positively given past trial participation and interest in participating in HD surveys. However, the findings from this study can be used to strengthen informed consent during HD clinical trial recruitment. Show more

Keywords: Huntington’s disease, clinical trial, clinical research, therapeutic misconception

DOI: 10.3233/JHD-190382

Citation: Journal of Huntington's Disease, vol. 8, no. 4, pp. 421-430, 2019

Authors: de Bot, Susanne Tamara

Article Type: Article Commentary

Abstract: The Huntington’s disease (HD) community is moving into an exciting time with Huntingtin lowering strategies entering human clinical trials. These upcoming targeted therapeutic approaches for this devastating disease with unmet medical needs, are believed to be a last resort for many patients and their families. Recently, patients with HD were shown to be at high risk for therapeutic misconception, mistaking research for actual treatment. It is important that investigators are aware of their patient’s, as well as their own, vulnerability to therapeutic misconception. To limit therapeutic misconception, information should be provided on the rationale for clinical trials and the differences …between clinical research and clinical care should be carefully discussed. Show more

Keywords: Huntington’s disease, therapeutic misconception clinical trial

DOI: 10.3233/JHD-199006

Citation: Journal of Huntington's Disease, vol. 8, no. 4, pp. 431-433, 2019

Authors: Kayson, Elise | Eberly, Shirley | Anderson, Karen E. | Marder, Karen | Shoulson, Ira | Oakes, David | Young, Anne B. | Biglan, Kevin | Hersch, Steven | on behalf of The Huntington Study Group PHAROS Investigators

Article Type: Research Article

Abstract: Background: There is limited understanding of the feasibility of conducting long-term research among undiagnosed (pre-symptomatic) adults at risk to develop Huntington disease (HD), while protecting their emotional well-being and safety. Objective: To assess pre-specified events pertaining to emotional well-being, safety, and feasibility among healthy consenting adults at risk for developing HD who have chosen not to undergo genetic testing. Methods: PHAROS research participants prospectively reported the occurrence of events pertaining to psychological distress (psychiatric evaluations, depression, suicidality) and feasibility (maintaining confidentiality, study attrition). PHAROS enrolled 1001 participants. Results: Events pertaining to psychological distress were …reported by 35% of participants. The most common events included heightened suicide risk (26%), new onset depression (12%), and new mental health evaluation (9%); all occurred significantly more frequently among participants with expanded trinucleotide CAG repeats (≥37). Five deaths occurred, none related to suicide. Forty-one percent of participants reported self-disclosure of their HD at-risk status, and 15% reported that someone else (usually a family member) had done so. Confidentiality of CAG test results was maintained by investigators. The withdrawal rate was largely uniform over the study period and did not differ significantly by gender or CAG status. Conclusions: The potentially vulnerable research participants in PHAROS showed good emotional tolerability and safety. Individual CAG data were not disclosed, and confidentiality about disclosure of at-risk HD status was well maintained by others (family, friends, etc.). Long-term research participation of adults at risk for HD who choose not to undergo pre-symptomatic DNA testing is well tolerated, safe and feasible. Show more

Keywords: Huntington’s disease, at risk, psychological stressors, genetic privacy, observational trial

DOI: 10.3233/JHD-190365

Citation: Journal of Huntington's Disease, vol. 8, no. 4, pp. 435-441, 2019

Authors: Clever, Faye | Cho, In Ki | Yang, Jingjing | Chan, Anthony W.S.

Article Type: Research Article

Abstract: The expanded CAG repeat results in somatic mosaicism and genetic anticipation in Huntington’s disease (HD). Here we report a longitudinal study examining CAG repeat instability in lymphocytes and sperm of three HD monkeys throughout their whole life-span that encompass the prodromal to symptomatic stages of HD. We demonstrate a progressive increase in CAG repeat length in lymphocytes and sperm as the animals aged. We also examined the impact of CAG repeat length on expansion rate, which showed a clear linear correlation up to 62Q, and high instability after. Our findings stress the importance of further investigation in CAG instability …in peripheral blood cells longitudinally. Show more

Keywords: CAG instability, HD monkey, longitudinal, peripheral blood, sperm

DOI: 10.3233/JHD-190359

Citation: Journal of Huntington's Disease, vol. 8, no. 4, pp. 443-448, 2019

Authors: He, Yanqing | Suofu, Yalikun | Yablonska, Svitlana | Wang, Xiaoming | Larkin, Timothy M. | Kim, Jinho | Carlisle, Diane L. | Friedlander, Robert M.

Article Type: Research Article

Abstract: Background: Selective serotonin reuptake inhibitors (SSRIs) target the serotonin transporter (SERT) and are commonly prescribed for depression in Huntington’s disease (HD) patients. However, SERT expression in HD has not been carefully evaluated in patients or mouse models. Objective: In this study, we investigated SERT levels in HD patients and HD mouse models. Methods: We obtained HD patient brain striatal samples and matched controls, as well as brain tissue from CAG140 and R6/2 mice. SERT mRNA and protein levels were analyzed using quantitative RT-PCR and immunoblotting. Results and Conclusions: We found that SERT protein, but …not mRNA is markedly increased in grade 4 HD patient striatal tissue. These findings suggest posttranscriptional or translational SERT dysregulation as a possible etiologic factor modulating psychopathology in HD. Interestingly, SERT expression is variable in mouse models of the disease. Increased SERT levels are demonstrated in the brain of CAG140 mice, a full-length knock-in mouse model of the disease, but not in the striatum of the R6/2 fragment murine model of the disease. Based on this parameter, the CAG140 huntingtin knock-in mouse model is more suitable than the R6/2 model for the study of serotonergic pathway pathology in Huntington’s disease. Show more

Keywords: Huntington’s disease, murine models, serotonin, serotonin transporter

DOI: 10.3233/JHD-180318

Citation: Journal of Huntington's Disease, vol. 8, no. 4, pp. 449-457, 2019

Authors: Van Etten, Emily J. | Graves, Lisa V. | Taylor, Brad | Holden, Heather M. | Lopez, Francesca V. | Williams, McKenna E. | Pirogovsky-Turk, Eva | Corey-Bloom, Jody | Filoteo, J. Vincent | Delis, Dean C. | Gilbert, Paul E.

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) and Huntington’s disease (HD) are two neurodegenerative diseases affecting frontal-striatal function and memory ability. Studies using the original California Verbal Learning Test (CVLT) to examine recall and recognition abilities between these groups have produced mixed findings. Some found that individuals with HD demonstrate worse recall and recognition than those with PD, whereas others reported comparable performance. Objective: We utilized multiple indices of recall and recognition discriminability, provided by the second and third editions of the CVLT (CVLT-II and CVLT-3, respectively), that allow for a more thorough assessment of more nuanced aspects of verbal memory …function. Methods: We examined differences between individuals with PD (n  = 72) and those with HD (n  = 77) on CVLT-II indices of recall discriminability (immediate, short delay free and cued, long delay free and cued) and recognition discriminability (total, source, semantic, and novel) using standardized scores while controlling for education and Dementia Rating Scale-2 scores. Results: The HD group performed significantly worse than the PD group on all measures of recall and recognition discriminability (p s < 0.05), and group differences were associated with large Cohen’s d effect sizes. Conclusions: Our findings suggest that individuals with HD are more impaired than individuals with PD in more nuanced aspects of recall and recognition memory function. These CVLT indices yield more thorough assessments of recall and recognition memory function and have the potential to improve efforts to characterize and distinguish profiles of memory loss in different neurodegenerative populations, including PD and HD. Show more

Keywords: Parkinson’s disease, Huntington’s disease, California Verbal Learning Test, verbal memory, recall, recognition, discriminability

DOI: 10.3233/JHD-190346

Citation: Journal of Huntington's Disease, vol. 8, no. 4, pp. 459-465, 2019

Authors: Carlozzi, Noelle E. | Goodnight, Siera | Kratz, Anna L. | Stout, Julie C. | McCormack, Michael K. | Paulsen, Jane S. | Boileau, Nicholas R. | Cella, David | Ready, Rebecca E.

Article Type: Research Article

Abstract: Background: Patient-reported outcomes (PROs) for mental health are important for persons with Huntington disease (HD) who commonly experience symptoms of depression, anxiety, irritability, anger, aggression, and apathy. Given this, there is a need for reliable and valid patient-reported outcomes measures of mental health for use as patient-centered outcomes in clinical trials. Objective: Thus, the purpose of this study was to establish the psychometric properties (i.e., reliability and validity) of six Neuro-QoL and PROMIS mental health measures to support their clinical utility in persons with HD. Methods: 294 individuals with premanifest (n  = 102) or manifest HD (n … = 131 early HD; n  = 61 late HD) completed Neuro-QoL/PROMIS measures of Emotional and Behavioral Dyscontrol, Positive Affect and Well-Being, Stigma, Anger, Anxiety, and Depression, legacy measures of self-reported mental health, and clinician-rated assessments of functioning. Results: Convergent validity and discriminant validity for the Neuro-QoL and PROMIS measures of Emotional and Behavioral Dyscontrol, Positive Affect and Well-Being, Stigma, Anger, Anxiety, and Depression, were supported in persons with HD. Neuro-QoL measures of Anxiety and Depression also demonstrated moderate sensitivity and specificity (i.e., they were able to distinguish between individuals with and without clinically significant anxiety and depression). Conclusions: Findings provide psychometric support for the clinical utility of the Neuro-QoL/PROMIS measures of mental health measures in persons with HD. As such, these measures should be considered for the standardized assessment of health-related quality of life in persons with HD. Show more

Keywords: Neuro-QoL, PROMIS, emotion, mental health, validity, reliability, Huntington disease

DOI: 10.3233/JHD-190364

Citation: Journal of Huntington's Disease, vol. 8, no. 4, pp. 467-482, 2019

Authors: Medzech, Sabrina | Sass, Christian | Bohlen, Stefan | Lange, Herwig W. | Koch, Raphael | Schubert, Robin | Ringelstein, E. Bernd | Reilmann, Ralf

Article Type: Research Article

Abstract: Background: Assessment of motor symptoms in Huntington’s disease (HD) is based on the Unified-HD-Rating-Scale-Total-Motor-Score (UHDRS-TMS). Its categorical and rater-dependent nature reduces the ability to detect subtle changes and often placebo effects have been observed in trials. We have previously shown that impairments in isometric force matching can be detected by quantitative motor (Q-Motor) assessments of tongue protrusion forces (glossomotography) in HD. Objective: We aimed to investigate whether similar impairments in isometric force matching can be detected in tasks assessing hand and foot force coordination and whether correlations with clinical measures and the disease burden score can be found. …Methods: Using a pre-calibrated force transducer, the ability of subjects to generate and maintain isometric forces at different target levels displayed on a monitor was assessed. Target forces applied in the hand were 1.5 and 5 Newton [N] and in feet 1, 5, and 10 N. Subjects with HD (n  = 31) and age-matched controls (n  = 22) were recruited from the HD out-patient clinic. Results: All paradigms distinguished controls from HD. The static coefficient of variability (%) was the most robust measure across all matching tasks. Correlations with clinical measures, such as the UHDRS-TMS, TFC, and the DBS were found. Conclusions: Assessment of hand and foot force matching tasks was feasible and provided quantitative objective measures for severity of motor phenotype in HD. Since both upper and lower extremity motor function are relevant for everyday activities, these measures should be further assessed as candidates for developing functionally meaningful quantitative motor tasks. Show more

Keywords: Motor, endpoint, function, hand, foot, Huntington’s disease

DOI: 10.3233/JHD-190354

Citation: Journal of Huntington's Disease, vol. 8, no. 4, pp. 483-492, 2019