Journal of Huntington's Disease - Volume 9, issue 1

Authors: Burnip, Emma | Wallace, Emma | Gozdzikowska, Kristin | Huckabee, Maggie-Lee

Article Type: Review Article

Abstract: Background: Corticobulbar symptoms have been reported in all stages of Huntington’s disease (HD); aspiration pneumonia associated with swallowing impairment has been identified as the most common cause of death. Whilst recent research has described positive effects of corticobulbar rehabilitation in other neurodegenerative conditions, it is unclear if this is similarly effective in HD. Preliminary evidence in corticospinal rehabilitation has revealed physical therapy and exercise could be beneficial for individuals with HD. Objective: This systematic review will explore the literature relative to rehabilitation of corticobulbar symptoms in adults with HD. Methods: Two investigators independently searched relevant electronic …databases for literature related to corticobulbar rehabilitation in HD, published in English until October 2019. Included studies were critically appraised using the Oxford Centre for Evidence-based Medicine Levels of Evidence, Cochrane Risk of Bias Tool and Scottish Intercollegiate Guidelines Network checklists. Study outcomes included measurements of function, quality of life or neuromuscular physiology. Results: Seventy-seven publications were screened with eight studies meeting the inclusion criteria – two randomised control trials and six intervention studies. Validated and objective outcome measures of corticobulbar symptoms were infrequently used. There was a high risk of bias identified in 7/8 studies. The data suggested positive clinical outcomes, no adverse effects and no deterioration observed across longitudinal studies. Conclusions: This systematic review documented a lack of high-quality evidence to support the use of rehabilitation to treat corticobulbar symptoms in HD. However, the suggestion of potential positive effects based on available, albeit limited, studies provides justification for further research in this area. Show more

Keywords: Huntington’s disease, bulbar, dysphagia, swallowing, speech, dysarthria, treatment, rehabilitation

DOI: 10.3233/JHD-190384

Citation: Journal of Huntington's Disease, vol. 9, no. 1, pp. 1-12, 2020

Authors: Ghavami, Afshin | Olsen, Michael | Kwan, Mei | Beltran, Jose | Shea, John | Ramboz, Sylvie | Duan, Wenzhen | Lavery, Daniel | Howland, David | Park, Larry C.

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is a progressive neurodegenerative disorder that prominently affects the basal ganglia, leading to affective, cognitive, behavioral, and motor decline. The primary site of neuron loss in HD is the striatal part of the basal ganglia, with GABAergic medium size spiny neurons (MSNs) being nearly completely lost in advanced HD. Objective: Based on the hypothesis that mutant huntingtin (mHTT) protein injures neurons via transcriptional dysregulation, we set out to establish a transcriptional profile of HD disease progression in the well characterized transgenic mouse model, R6/2, and two Knock-in models (KI); zQ175KI (expressing mutant mouse/human chimeric …Htt protein) and HdhQ200 HET KI (carrying one allele of expanded mouse CAG repeats). Methods: In this study, we used quantitative PCR (qPCR) to evaluate striatal mRNA levels of markers of neurotransmission, neuroinflammation, and energy metabolism. Results: After analyzing and comparing transcripts from pre-symptomatic and symptomatic stages, markers expressed in the basal ganglia MSNs, which are typically involved in maintaining normal neurotransmission, showed a genotype-specific decrease in mRNA expression in a pattern consistent with human studies. In contrast, transcripts associated with neuroinflammation and energy metabolism were mostly unaffected in these animal models of HD. Conclusion: Our results show that transcripts linked to neurotransmission are significantly reduced and are consistent with disease progression in both zQ175KI and R6/2 transgenic mouse models. Show more

Keywords: Huntington’s disease, MSNs, mHTT, transcriptional dysregulation, qPCR

DOI: 10.3233/JHD-190389

Citation: Journal of Huntington's Disease, vol. 9, no. 1, pp. 13-31, 2020

Authors: Cabanas, Magali | Piquemal, Marion | Pistono, Cristiana | Arnaud, Syndelle | Rakesh, Divyangana | Poinama, Elodie | Guillou, Jean-Louis | Garret, Maurice | Cho, Yoon H.

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is a neurodegenerative disorder caused by the expansion of the trinucleotide CAG in the HD gene. While the presence of nuclear aggregates of mutant huntingtin (mHtt) in neurons is a hallmark of HD, the reason behind its toxicity remains elusive. Objective: The present study was conducted to assess a correlation between the number of mHtt aggregates and the severity of HD symptoms in R6/1 mice. Methods: We investigated correlations between behavioral deficits and the level of nuclear mHtt aggregates in different neuroanatomical regions in 3-month-old R6/1 mice, the age at which a …large variability of symptom severity between animals has been observed. Results: R6/1 mice were deficient in instinctive and anxiety related behaviors as well as long-term memory capabilities. Significant differences were also found between the sexes; female transgenic mice displayed less severe deficits than males. While the level of mHtt aggregates was correlated with the severity of HD phenotypes in most regions of interest, an opposite relationship also was found for some other regions examined. Conclusions: The obtained results suggest harmful and region-specific roles of mHtt aggregates in HD symptoms. Show more

Keywords: Mutant huntingtin aggregates, motor activity, short-term and long-term memory, spatial memory, anxiety, instinctive behavior, R6/1 mice

DOI: 10.3233/JHD-190352

Citation: Journal of Huntington's Disease, vol. 9, no. 1, pp. 33-45, 2020

Authors: McGarry, Andrew | McDermott, Michael P. | Kieburtz, Karl | Peng, Jing | Cudkowicz, Merit | for the Huntington Study Group 2CARE Investigators and Coordinators

Article Type: Research Article

Abstract: Background: Despite the clearly recognized progressive functional decline of Huntington’s disease (HD), detailed investigations of factors associated with the rate of functional progression are limited. Objective: Understanding factors associated with functional decline through examination of existing HD clinical databases may improve efforts to mitigate it. Methods: We analyzed data from 2CARE, a randomized clinical trial with up to 5 years of follow-up, to assess potential risk factors for more rapid functional decline in HD. Results: Variables associated with faster functional decline included worse motor performance, worse cognitive test scores, female sex, lower weight and …body mass index, and a higher CAG repeat length, especially in younger people. Conclusion: While our data are limited to the structured environment and homogeneity of a clinical trial, attention to several of the identified risk factors may be useful towards managing functional decline over time. The observation that women progress faster than men, while potentially confounded by an association between sex and weight, deserves further study. Show more

Keywords: Huntington’s disease, clinical trial, functional decline, total functional capacity

DOI: 10.3233/JHD-190391

Citation: Journal of Huntington's Disease, vol. 9, no. 1, pp. 47-58, 2020

Authors: Ringkøbing, Signe Pertou | Larsen, Ida Unmack | Jørgensen, Kasper | Vinther-Jensen, Tua | Vogel, Asmus

Article Type: Research Article

Abstract: Background: Due to high prevalence of cognitive impairment in Huntington’s disease (HD) gene mutation carriers, even before onset of motor symptoms, cognitive screening is important for the optimal management of patients. The Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) are widely used, but the validity for HD has only been evaluated in few studies with important limitations. Objective: To evaluate the discriminative validity of the MMSE and the MoCA for the assessment of cognitive dysfunction in HD gene mutation carriers, independently of motor manifestation and furthermore, to report estimated probabilities for cognitive impairment with different score …ranges on the MMSE and the MoCA. Methods: 106 pre-motor-manifest and motor-manifest HD gene mutation carriers and 40 non-HD gene mutation carriers were administered the MMSE, the MoCA, and an extensive neuropsychological battery with operationalized criteria for cognitive impairment. The same physician and the same neuropsychologist performed all examinations; blinded to one another. Results: The area under the receiver operating characteristic (ROC) curve was 0.70 for the MMSE and 0.82 for the MoCA. The latter correctly diagnosed 82% of the cognitively impaired and not-impaired HD gene mutation carriers and non-HD gene mutation carriers, whereas the MMSE only diagnosed 73% correctly. Conclusions: The MMSE and the MoCA can both be used as cognitive screening tests in HD gene mutation carriers, but both have important limitations. Our results indicate that the MoCA is a better cognitive screening test for HD than the MMSE. In addition, our study provides estimated probabilities for cognitive impairment with different score ranges, which may be used as clinical guidelines in the interpretation of results from the two tests. Show more

Keywords: Huntington’s disease, cognitive dysfunction, Mini-Mental State Examination, Montreal Cognitive Assessment

DOI: 10.3233/JHD-190350

Citation: Journal of Huntington's Disease, vol. 9, no. 1, pp. 59-68, 2020

Authors: Dinesh, Karthik | Snyder, Christopher W. | Xiong, Mulin | Tarolli, Christopher G. | Sharma, Saloni | Dorsey, E. Ray | Sharma, Gaurav | Adams, Jamie L.

Article Type: Research Article

Abstract: Background: Most current measures of Huntington’s disease (HD) motor symptoms are subjective, categorical, and limited to in-person visits. Wearable sensors enable objective, frequent, and remote data collection in real-world settings. However, longitudinal sensor studies in HD are lacking. Objective: To measure motor symptoms of HD using wearable sensors in a longitudinal study. Methods: Participants with HD, prodromal HD, and without a movement disorder wore five accelerometers, one on each limb and on the trunk, at up to four clinic visits over one year. After each visit, participants wore the sensors at home for two days. Based …on the accelerometer data from the trunk, we calculated a “truncal Chorea Index” for periods when the participant was sitting. We also measured gait parameters and activity profiles. To measure group differences, track progression, and observe individual variability, statistical analysis of the data was conducted using a linear mixed-effects model. Results: Fifteen individuals with HD, five with prodromal HD, and 19 controls were enrolled. The average truncal Chorea Index was higher in individuals with HD (26.6, p  < 0.001) than in controls (15.6). For participants with HD, the truncal Chorea Index showed a high intra-day variability but minimal change over 12 months. Individuals with HD walked less (HD = 3818, prodromal HD = 6957, controls = 5514 steps/day) and took longer duration steps (HD = 0.97, prodromal HD = 0.78, controls = 0.85 seconds/step) than the other groups. Individuals with HD spent over half their day lying down (HD = 51.1%, prodromal HD = 38.0%, controls = 37.1%). Conclusions: A novel truncal Chorea Index can assess truncal chorea at home, finds substantial variability, and suggests that truncal chorea may be present in prodromal HD. Individuals with HD walk less and slower and spend more time lying down than controls. These findings require additional investigation, could inform clinical care, and could be used to evaluate new therapies. Show more

Keywords: Huntington’s disease, chorea, motor activity, gait, wearable electronic devices, walking speed

DOI: 10.3233/JHD-190375

Citation: Journal of Huntington's Disease, vol. 9, no. 1, pp. 69-81, 2020

Authors: Carlozzi, Noelle E. | Boileau, Nicholas R. | Hahn, Elizabeth A. | Barton, Stacey K. | Cella, David | McCormack, Michael K. | Ready, Rebecca E.

Article Type: Research Article

Abstract: Background: Social health is an important concern in persons with Huntington’s disease (HD); however, there is little literature examining this construct in this population. Objective: While cross-sectional data supports the clinical utility of two Neuro-QoL social health measures in persons with HD, data is still needed to establish their longitudinal validity. Methods: Participants (N  = 358) completed baseline and at least one follow-up (12- and 24-month) assessment that included the completion of Neuro-QoL Social Health computer adaptive tests (CATs) and short forms (for Ability to Participate in Social Roles and Activities [SRA] and Satisfaction with SRA). Test-retest …reliability was examined using intra class correlations, and one-way ANOVAs with Bonferroni post-hoc contrasts were used to determine whether there were group differences among premanifest, early- and late-stage HD participants on the Social health measures. In addition, standardized response means were used to examine longitudinal responsiveness, and mixed or general linear models were used to examine change over time (relative to self-reported change on an associated anchor item about social health and clinician-rated change based on Total Functional Capacity scores from the UHDRS). Results: Test-retest reliability of the measures was excellent (ICCs ranged from 0.82 to 0.87 across the different measures) and persons with greater disease burden reported more problems with social health than those at earlier stages in the disease process (all p  < 0.0001). Responsiveness was supported for all measures except the Ability to Participate in SRA CAT; participants who had self-reported or clinician-rated declines in health generally had 12- and 24-month declines on the Neuro-QoL measures. Conclusions: Findings indicate that these measures may be useful for studies attempting to assess change in social health over time. Show more

Keywords: Huntington’s disease, patient-reported outcomes, health-related quality of life, social health, validity

DOI: 10.3233/JHD-190385

Citation: Journal of Huntington's Disease, vol. 9, no. 1, pp. 83-97, 2020

Authors: Hergert, Danielle C. | Sanchez-Ramos, Juan | Cimino, Cynthia R.

Article Type: Research Article

Abstract: Background: Anosognosia, or unawareness of illness of deficits, has been observed in Huntington’s disease (HD) in relation to motor and cognitive signs and symptoms. Most studies of awareness in HD have used self-report questionnaire methodology rather than asking patients to report on their symptoms in real-time. The two studies in which patients were asked about their chorea in real-time had small sample sizes and only examined patients early in disease progression. Objective: To examine awareness of chorea in real-time in HD patients across a broad range of disease progression. Methods: Fifty HD patients across motor and …cognitive impairment severity were asked if they noticed any involuntary movements after completing a simple working memory task used to elicit chorea. A movement disorders specialist rated the presence or absence of chorea while the patients completed the task. Disagreement between the patient and movement disorders specialist’s ratings was considered to be an indicator of unawareness. Results: Approximately 46% of patients who exhibited chorea did not report chorea. Eighty-eight percent of participants who acknowledged chorea did not report chorea in all parts of the body that chorea was observed. Conclusions: HD patients demonstrate unawareness of chorea across cognitive and motor sign severity. Show more

Keywords: Anosognosia, basal ganglia, chorea, Huntington’s disease

DOI: 10.3233/JHD-190381

Citation: Journal of Huntington's Disease, vol. 9, no. 1, pp. 99-103, 2020

Article Type: Meeting Report

DOI: 10.3233/JHD-200001

Citation: Journal of Huntington's Disease, vol. 9, no. 1, pp. 105-105, 2020