Journal of Huntington's Disease - Volume 10, issue 4

Authors: Patino, Jorge | Karagas, Nicholas E. | Chandra, Shivika | Thakur, Nivedita | Stimming, Erin Furr

Article Type: Review Article

Abstract: Olfactory dysfunction is a common symptom in patients with neurodegenerative disorders, including Huntington’s disease (HD). Understanding its pathophysiology is important in establishing a preventive and therapeutic plan. In this literature review, we cover the physiology of olfaction, its role in neurodegeneration, and its characteristics in patients with HD. In the general population, olfactory dysfunction is present in 3.8–5.8%and the prevalence increases significantly in those older than 80 years. For HD, data regarding prevalence rates are lacking and the scales used have been inconsistent or have been restructured due to concerns about cross-cultural understanding. Pathogenic huntingtin deposits have been found in …the olfactory bulb of individuals with HD, although no studies have correlated this with the grade of olfactory impairment. Olfactory dysfunction is present in both premanifest and manifest patients with HD, showing a progressive decline over time with more severe deficits at advanced stages. No specific treatment for olfactory impairment in HD has been proposed; identifying and avoiding potential medications that cause olfactory dysfunction, as well as general safety recommendations remain the basis of the therapeutic strategy. Show more

Keywords: Huntington’s disease, olfaction disorders, smell, neurodegenerative diseases

DOI: 10.3233/JHD-210497

Citation: Journal of Huntington's Disease, vol. 10, no. 4, pp. 413-422, 2021

Authors: Mears, Emily R. | Handley, Renee R. | Grant, Matthew J. | Reid, Suzanne J. | Day, Benjamin T. | Rudiger, Skye R. | McLaughlan, Clive J. | Verma, Paul J. | Bawden, Simon C. | Patassini, Stefano | Unwin, Richard D. | Cooper, Garth J.S. | Gusella, James F. | MacDonald, Marcy E. | Brauning, Rudiger | Maclean, Paul | Pearson, John F. | Waldvogel, Henry J. | Faull, Richard L.M. | Snell, Russell G.

Article Type: Research Article

Abstract: Background: The pathological mechanism of cellular dysfunction and death in Huntington’s disease (HD) is not well defined. Our transgenic HD sheep model (OVT73) was generated to investigate these mechanisms and for therapeutic testing. One particular cohort of animals has undergone focused investigation resulting in a large interrelated multi-omic dataset, with statistically significant changes observed comparing OVT73 and control ‘omic’ profiles and reported in literature. Objective: Here we make this dataset publicly available for the advancement of HD pathogenic mechanism discovery. Methods: To enable investigation in a user-friendly format, we integrated seven multi-omic datasets from a cohort …of 5-year-old OVT73 (n  = 6) and control (n  = 6) sheep into a single database utilising the programming language R. It includes high-throughput transcriptomic, metabolomic and proteomic data from blood, brain, and other tissues. Results: We present the ‘multi-omic’ HD sheep database as a queryable web-based platform that can be used by the wider HD research community (https://hdsheep.cer.auckland.ac.nz/ ). The database is supported with a suite of simple automated statistical analysis functions for rapid exploratory analyses. We present examples of its use that validates the integrity relative to results previously reported. The data may also be downloaded for user determined analysis. Conclusion: We propose the use of this online database as a hypothesis generator and method to confirm/refute findings made from patient samples and alternate model systems, to expand our understanding of HD pathogenesis. Importantly, additional tissue samples are available for further investigation of this cohort. Show more

Keywords: Huntington’s disease, animal models, sheep, metabolomics, database, RNA-seq, proteomics, systems biology, genetics, computational biology

DOI: 10.3233/JHD-210482

Citation: Journal of Huntington's Disease, vol. 10, no. 4, pp. 423-434, 2021

Authors: Braatz, Elise M. | André, Emily A. | Liu, Jeh-Ping | Zeitlin, Scott O.

Article Type: Research Article

Abstract: Background: The Huntingtin (HTT) N-terminal domains encoded by Huntingtin ’s (HTT ) exon 1 consist of an N17 domain, the polyglutamine (polyQ) stretch and a proline-rich region (PRR). These domains are conserved in mammals and have been hypothesized to modulate HTT’s functions in the developing and adult CNS, including DNA damage repair and autophagy. Objective: This study longitudinally characterizes the in vivo consequences of deleting the murine Htt N-terminal domains encoded by Htt exon 1. Methods: Knock-in mice with a deletion of Htt exon 1 sequences (Htt ΔE 1 ) were generated …and bred into the C57BL/6J congenic genetic background. Their behavior, DNA damage response, basal autophagy, and glutamatergic synapse numbers were evaluated. Results: Progeny from Htt ΔE 1/+ intercrosses are born at the expected Mendelian frequency but with a distorted male to female ratio in both the Htt ΔE 1/ΔE 1 and Htt +/+ offspring. Htt ΔE 1/ΔE 1 adults exhibit a modest deficit in accelerating rotarod performance, and an earlier increase in cortical and striatal DNA damage with elevated neuronal pan-nuclear 53bp1 levels compared to Htt +/+ mice. However, a normal response to induced DNA damage, normal levels of basal autophagy markers, and no significant differences in corticocortical, corticostriatal, thalamocortical, or thalamostriatal synapses numbers were observed compared to controls. Conclusion: Our results suggest that deletion of the Htt N-terminus encoded by the Htt exon 1 does not affect Htt’s critical role during embryogenesis, but instead, may have a modest effect on certain motor tasks, basal levels of DNA damage in the brain, and Htt function in the testis. Show more

Keywords: Huntingtin, huntingtin exon 1, DNA damage, autophagy, sex ratio

DOI: 10.3233/JHD-210494

Citation: Journal of Huntington's Disease, vol. 10, no. 4, pp. 435-454, 2021

Authors: Story, Darren | Gallien, John | Al-Gharaibeh, Abeer | Sandstrom, Michael | Rossignol, Julien | Dunbar, Gary L.

Article Type: Short Communication

Abstract: The R6/2 murine model of Huntington’s disease (HD) is extensively used in HD research. The current study replicates and extends previous work assessing the impact of housing R6/2 mice with healthy wild-type (WT) littermates on disease progression. The current study extends the previous finding by including male cohorts and the use of a standard diet and water regimen, as opposed to the enhanced diet used in the previous study. This study found that the inclusion of healthy wild-type (WT) littermates, alone, improved survivabilty in R6/2 mice, but did not have a significant impact on weight loss.

Keywords: R6/2, Huntington’s disease, environmental enrichment, survivability, housing

DOI: 10.3233/JHD-210474

Citation: Journal of Huntington's Disease, vol. 10, no. 4, pp. 455-458, 2021

Authors: Horta-Barba, Andrea | Martinez-Horta, Saul | Perez-Perez, Jesús | Sampedro, Frederic | de Lucia, Natascia | De Michele, Giuseppe | Salvatore, Elena | Kehrer, Stefanie | Priller, Josef | Migliore, Simone | Squitieri, Ferdinando | Castaldo, Anna | Mariotti, Caterina | Mañanes, Veronica | Lopez-Sendon, Jose Luis | Rodriguez, Noelia | Martinez-Descals, Asunción | Júlio, Filipa | Janurio, Cristina | Delussi, Marianna | de Tommaso, Marina | Noguera, Sandra | Ruiz-Idiago, Jesus | Sitek, Emilia J. | Wallner, Renata | Nuzzi, Angela | Pagonabarraga, Javier | Kulisevsky, Jaime | on behalf the Cognitive Phenotype Working Group of the European Huntington’s Disease Network

Article Type: Research Article

Abstract: Background: Arithmetic word-problem solving depends on the interaction of several cognitive processes that may be affected early in the disease in gene-mutation carriers for Huntington’s disease (HD). Objective: Our goal was to examine the pattern of performance of arithmetic tasks in premanifest and manifest HD, and to examine correlations between arithmetic task performance and other neuropsychological tasks. Methods: We collected data from a multicenter cohort of 165 HD gene-mutation carriers. The sample consisted of 31 premanifest participants: 16 far-from (>12 years estimated time to diagnosis; preHD-A) and 15 close-to (≤12 years estimated time to diagnosis; preHD-B), …134 symptomatic patients (early-mild HD), and 37 healthy controls (HC). We compared performance between groups and explored the associations between arithmetic word-problem solving and neuropsychological and clinical variables. Results: Total arithmetic word-problem solving scores were lower in preHD-B patients than in preHD-A (p  < 0.05) patients and HC (p  < 0.01). Early-mild HD patients had lower scores than preHD patients (p  < 0.001) and HC (p  < 0.001). Compared to HC, preHD and early-mild HD participants made more errors as trial complexity increased. Moreover, arithmetic word-problem solving scores were significantly associated with measures of global cognition (p  < 0.001), frontal-executive functions (p  < 0.001), attention (p  < 0.001) visual working memory (p  < 0.001), mental rotation (p  < 0.001), and confrontation naming (p  < 0.05). Conclusion: Arithmetic word-problem solving is affected early in the course of HD and is related to deficient processes in frontal-executive and mentalizing-related processes. Show more

Keywords: Huntington’s disease, cognition, arithmetic, neuropsychology, word-problem solving, acalculia

DOI: 10.3233/JHD-210480

Citation: Journal of Huntington's Disease, vol. 10, no. 4, pp. 459-468, 2021

Authors: Gavrielov-Yusim, Natalie | Barer, Yael | Martinec, Michael | Siadimas, Athanasios | Roumpanis, Spyros | Furby, Hannah | Goldshtein, Inbal | Jan, Asif | Coloma, Preciosa M.

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is a rare, genetic, neurodegenerative disease. Obtaining population-level data on epidemiology and disease management is challenging. Objective: To investigate the epidemiology, clinical manifestations, treatment, and healthcare utilization of patients with HD in Israel. Methods: Retrospective population-based cohort study, including 20 years of routinely collected data from Maccabi Healthcare Services, an insurer and healthcare provider for one-quarter of the Israeli population. Results: The study cohort included 109 adult patients (aged ≥18 years) diagnosed with HD, with mean age of 49.9 years and 56%females. The most common HD-related conditions were anxiety (40%), …behavioral problems (34%), sleep disorders (21%), and falls (13%). Annual incidence rates for HD ranged from 0.17 to 1.34 per 100,000 from 2000 to 2018; the 2018 crude prevalence in adults was 4.36 per 100,000. Median survival from diagnosis was approximately 12 years (95%CI: 10.4–15.3). The most frequent symptomatic treatments were antidepressants (69%), antipsychotics (63%), and tetrabenazine (63%), the only drug approved for the treatment of HD chorea in Israel during the examined period. Patterns of healthcare utilization changed as disease duration increased, reflected by increased frequency of emergency department visits and home visits. Conclusion: This retrospective population-based study provides insights into the prevalence, incidence, clinical profile, survival, and resource utilization of patients with HD in ethnically diverse Israel. The findings in this study are generally consistent with the international literature and demonstrate the value of routinely collected healthcare data as a complementary resource in HD research. Show more

Keywords: Huntington’s disease, Israel, real-world data, healthcare resource utilization, treatment patterns

DOI: 10.3233/JHD-210500

Citation: Journal of Huntington's Disease, vol. 10, no. 4, pp. 469-477, 2021

Authors: Lee, Sean J. | Hale, Lisa M. | Huitz, Elizabeth | Claassen, Daniel O. | McDonell, Katherine E.

Article Type: Research Article

Abstract: Background: The COVID-19 pandemic has increased the need for remote healthcare options among patients with Huntington’s disease (HD). However, since not every HD patient is suitable for telehealth, it is important to differentiate who can be seen virtually from who should remain as in-person. Unfortunately, there are no clinical guidelines on how to evaluate HD patients for telehealth eligibility. Objective: To standardize the teleneurology selection process in HD by implementing a screening tool that accounts for patient-specific factors. Methods: We organized various indications and contraindications to teleneurology into a flowchart. If any indications or contraindications were …met, patients were assigned to telehealth or maintained as in-person, respectively. If no indications or contraindications were met, patients were given the option of telehealth or in-person for their upcoming appointments. In two implementation cycles, we tested this screening tool among all HD patients scheduled for clinic visits, aided by chart review and phone interview. Results: In a cohort of 81 patients, telehealth acceptance among eligible patients increased from 45.0%to 83.3%. Frequency of telehealth visits increased from a pre-intervention baseline of 12.8%to 28.2%. Conclusion: Teleneurology utilization among HD patients more than doubled across our study. Our intervention promotes consistency and patient-centeredness in HD clinical care and streamlines the overall telehealth selection process. Future studies can seek to reduce telehealth no-shows and also evaluate the utility of the motor and psychiatric criteria included in our screening tool. Show more

Keywords: Neurology, Huntington’s disease, pandemic, telehealth, standardization, flowchart

DOI: 10.3233/JHD-210498

Citation: Journal of Huntington's Disease, vol. 10, no. 4, pp. 479-484, 2021

Authors: Ogilvie, Amy C. | Nopoulos, Peg C. | Schultz, Jordan L.

Article Type: Research Article

Abstract: Background: Unintended weight loss and decreased body mass indexes (BMIs) are common symptoms of individuals with manifest HD. It is unknown at what point during disease progression weight loss starts to accelerate relative to a healthy individual’s weight and when recommended interventions should be initiated to have the strongest impact on patient care. Objective: The objective of this study was to identify a point in time relative to age at motor onset when the decline in weight in HD starts to accelerate relative to a non-HD population. The relationship between initiation of weight loss interventions and changes in …weight loss was also explored. Methods: Participants from the fifth version of the Enroll-HD study were identified for this research. Linear mixed-effects piecewise regression models were used to estimate the point in time relative to the reported age of motor onset in which BMI started to decline in participants with HD compared to healthy non-HD controls. A post-hoc descriptive analysis was performed to look at when nutritional supplements and swallow therapy were initiated in participants with HD relative to motor onset. Results: BMI decline in the HD group began to accelerate compared to controls approximately 5.7 years after the reported age of motor onset (95% CI: 4.7–6.9). The average initiation times of swallow therapy and nutritional supplements were 7.7 years (SD = 5.5 years) and 6.7 years (SD = 6.5 years) after motor onset, respectively. Conclusion: Our findings suggest a potential point for intervention of nutrition programs or therapies used to prevent future weight loss. Show more

Keywords: Huntington’s disease, disease progression, body-weight trajectory, weight loss

DOI: 10.3233/JHD-210488

Citation: Journal of Huntington's Disease, vol. 10, no. 4, pp. 485-492, 2021

Authors: Kalkers, Kristel | Schols, Jos M.G.A. | van Zwet, Erik W. | Roos, Raymund A.C.

Article Type: Research Article

Abstract: Background: Falls are common in Huntington’s disease (HD), which can have serious consequences and may therefore lead to fear of falling (FoF). There is little knowledge about falls or FoF in individuals with HD or about formal and informal caregivers’ fear about falls in individuals with HD. Objective: To explore prevalence of falls, FoF and fall preventive measures both those applied and those not included in managing falls in individuals with HD and their formal and informal caregivers, and to identify the relationship between FoF and, anxiety, awareness and cognitive functioning respectively. Methods: In a multi-center …observational cross-sectional study, care-independent and -dependent individuals with HD and their formal and informal caregivers were recruited from six Dutch nursing homes specialized in HD. The participants were assessed by means of questionnaires enquiring about falls, FoF, awareness of fall risk, cognition, anxiety and fall preventive measures. Results: For all included 158 individuals with HD, the fall prevalence over the last 30 days was 28.8%. The prevalence of FoF in individuals with HD, formal caregivers and informal caregivers was 47.6%, 25.6%, and 63.5%, respectively, for care-independent individuals with HD and 46.9%, 26.3%, and 62.0%, respectively, for care-dependent individuals with HD. Anticipatory awareness of fall risks and gender are predictors of FoF in care-independent individuals with HD, though not in the care-dependent group. A combination of fall preventive measures is used in most individuals with HD. Conclusion: Fall prevalence is high and FoF is common in individuals with HD and their caregivers. Gender and anticipatory awareness are risk factors for FoF. In addition to the use of individual multifactorial fall prevention strategies, it is important to support both formal and informal caregivers in coping with falls Show more

Keywords: Huntington’s disease, falls, fear, cognition, awareness, caregivers

DOI: 10.3233/JHD-210493

Citation: Journal of Huntington's Disease, vol. 10, no. 4, pp. 493-503, 2021