Journal of Huntington's Disease - Volume 9, issue 2

Authors: Karagas, Nicholas E. | Rocha, Natalia Pessoa | Stimming, Erin Furr

Article Type: Review Article

Abstract: Huntington’s disease (HD) is a heritable and fatal neurodegenerative disease characterized by a triad of motor, cognitive and neuropsychiatric symptoms. A common and particularly detrimental neuropsychiatric alteration in HD gene carriers is irritability, which frequently manifests as abrupt and unpredictable outbursts of anger. This symptom increases the burden of HD in multiple ways, such as jeopardizing employment and straining familial or caregiver support. Although irritability in HD is diagnosed by the administration of standardized rating scales and clinical expertise, measurement of severity and progression is complicated by several factors. Currently, individuals with HD who present with irritability may be managed …with a variety of psychotropic medications, primarily antidepressants and antipsychotics. While these therapies offer relief to individuals suffering from irritability in HD, they are often not sufficient. Here, we review irritability in the context of HD and emphasize the need for treatments that are better tailored to mitigate this troublesome symptom. An expeditious strategy in pursuit of this goal involves evaluating the efficacy of approved medications that are used to treat similar neuropsychiatric symptoms. Show more

Keywords: Huntington’s disease, irritable mood, neuropsychiatry, behavioral symptoms, psychotropic drugs

DOI: 10.3233/JHD-200397

Citation: Journal of Huntington's Disease, vol. 9, no. 2, pp. 107-113, 2020

Authors: Machiela, Emily | Southwell, Amber L.

Article Type: Review Article

Abstract: Huntington’s disease (HD) is a fatal, inherited neurodegenerative disorder caused by a mutation in the huntingtin gene (HTT ). While mutant HTT is present ubiquitously throughout life, HD onset typically occurs in mid-life, suggesting that aging may play an active role in pathogenesis. Cellular aging is defined as the slow decline in stress resistance and accumulation of damage over time. While different cells and tissues can age at different rates, 9 hallmarks of aging have emerged to better define the cellular aging process. Strikingly, many of the hallmarks of aging are also hallmarks of HD pathology. Models of HD and …HD patients possess markers of accelerated aging, and processes that decline during aging also decline at a more rapid rate in HD, further implicating the role of aging in HD pathogenesis. Furthermore, accelerating aging in HD mouse and patient-derived neurons unmasks HD-specific phenotypes, suggesting an active role for the aging process in the onset and progression of HD. Here, we review the overlap between the hallmarks of aging and HD and discuss how aging may contribute to pathogenesis in HD. Show more

Keywords: Biological aging, cellular aging, DNA damage, Huntington’s disease, microsatellite instability, neurodegeneration, oxidative stress, proteostasis, telomere

DOI: 10.3233/JHD-200395

Citation: Journal of Huntington's Disease, vol. 9, no. 2, pp. 115-128, 2020

Authors: Kjoelaas, Siri | Tillerås, Kristine Hansen | Feragen, Kristin Billaud

Article Type: Research Article

Abstract: Background: The average age for the onset of Huntington’s disease (HD) is an age when many people have children and caretaking responsibilities; HD is therefore likely to impact the whole family, including children and adolescents. Despite an increased understanding of the challenges for young people of growing up in a family affected by HD, a continuing lack of available knowledge has led to inadequate youth-focused support in many countries. Objective: This study explored the risks of growing up in a family affected by HD, and provided a participant-generated overview of the main challenges the participants experienced, in order …to enhance awareness and promote more youth-focused support. Methods: As part of a larger national study, this qualitative paper included 36 semi-structured interviews with young people and adults who had previous or current experiences of growing up in families affected by HD. The interviews were analysed using thematic analysis. Results: The participants described challenges relating to four main domains of everyday life: family functioning, emotions and reactions, social functioning, and public and care services. Conclusion: This study contributes to an increased understanding of risk factors posed on young people by growing up with a parent with HD. The study highlighted challenges in several areas of life presenting a risk to the overall health and functioning of young people. We propose that this knowledge should be applied within a bioecological framework, to increase understanding and promote awareness of the possible risks posed, for young people, by HD. Show more

Keywords: Awareness, challenges, Huntington’s disease, knowledge, qualitative research, support, young people

DOI: 10.3233/JHD-190377

Citation: Journal of Huntington's Disease, vol. 9, no. 2, pp. 129-141, 2020

Authors: Leitão, Ricardo | Guerreiro, Carla | Nunes, Rita G. | Gonçalves, Nilza | Galati, Giulia | Rosário, Madalena | Guedes, Leonor Correia | Ferreira, Joaquim J. | Reimão, Sofia

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder inducing motor, psychiatric changes and cognitive decline, characterized pathologically by striatal atrophy. Pathological changes in the extra-striatal structures, such as the substantia nigra (SN), and abnormalities in pre-synaptic striatal dopamine neurotransmission are also known to occur. Neuromelanin (NM)-sensitive magnetic resonance imaging (NM-MRI) is an innovative technique that was recently developed allowing the in vivo study of pathological changes in the dopaminergic neurons of the SN. Objective: To investigate the SN MR signal in HD patients. Methods: We performed a cross-sectional study using a specific T1-weighted MR …sequence to visualize NM. The areas and signal intensity contrast ratios of the T1 hyperintense SN regions were obtained using a semi-automatic segmentation method. Results: A total of 8 HD patients and 12 healthy subjects were evaluated. The SN area was markedly reduced in the HD group compared with the control group (p  = 0.02), even after normalization of the SN area with the midbrain area and age correction (p  = 0.01). There was a significant reduction in the intensity contrast ratio of the hyperintense SN areas to crus cerebri in HD patients comparing with controls (p  = 0.04) after correction for age. Conclusions: NM-sensitive MR techniques were used for the first time to study the SN in HD patients, showing loss of NM in this region, supporting the implication of dopaminergic neuronal changes in disease pathology. Future research needs to be conducted to evaluate the potential of SN area and intensity contrast as biomarkers for HD. Show more

Keywords: Huntington’s disease, neuromelanin-sensitive magnetic resonance imaging, neurodegeneration, substantia nigra

DOI: 10.3233/JHD-190388

Citation: Journal of Huntington's Disease, vol. 9, no. 2, pp. 143-148, 2020

Authors: Buren, Caodu | Tu, Gaqi | Raymond, Lynn A.

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by expansion of CAG repeats in the Huntingtin gene (HTT ). Studies suggest cortical to striatal (C-S) projections, which regulate movement and provide cell survival signals to SPNs, are altered in the pre-manifest and early symptomatic stages of HD. But whether and how presynaptic cortical terminals are affected in HD is not well explored. Objective: Test size and replenishment of readily releasable pool (RRP), and assess glutamate refill of C-S synapses in HD models. Methods: Immunocytochemistry was applied in C-S co-cultures generated from FVB/N (WT: wildtype) …mice and YAC128, an HD mouse model expressing human HTT with  128 CAG repeats on the FVB/N background; Whole-cell patch clamp recordings from striatal neurons were performed both in cultures, with or without osmotic stimuli, and in acute brain slices from 6-month-old early symptomatic YAC128 mice and WT following prolonged trains of electrical stimuli in corpus callosum. Results: We found no change in the average size or vesicle replenishment rate of RRP in C-S synapses of YAC128, compared with WT, cultures at day in vitro 21, a time when immunocytochemistry showed comparable neuronal survival between the two genotypes. However, YAC128 C-S synapses showed a slowed rate of recovery of glutamate release in co-cultures as well as in acute brain slices. Conclusion: Mutant HTT expression impairs glutamate refill but not RRP size or replenishment in C-S synapses. This work provides a foundation for examining the contribution of deficits in presynaptic cortical terminals on HD progression. Show more

Keywords: Cortical, presynaptic, readily releasable pool, glutamate refill

DOI: 10.3233/JHD-200400

Citation: Journal of Huntington's Disease, vol. 9, no. 2, pp. 149-161, 2020

Authors: Keage, Megan | Baum, Shira | Pointon, Lisa | Lau, Jane | Berndt, Jacinta | Hopkins, Josephine | Maule, Roxanne | Vogel, Adam P.

Article Type: Research Article

Abstract: Background: Dysphagia is common in Huntington’s disease (HD) affecting all phases of swallowing. Correlations exist between non-instrumental measures of dysphagia and clinical features of HD, including age, disease duration and degree of motor impairment. Lack of instrumental data limits our ability to wholly characterize HD-related dysphagia and prognosticate swallowing changes over time. Objective: To retrospectively describe a relatively large database of videofluoroscopic studies (VFSSs) and determine the relationships between dysphagia and HD clinical parameters, including disease duration and burden of pathology score. Methods: Medical and swallowing data of 49 individuals with HD and dysphagia were examined. …VFSS data were interpreted using the Bethlehem Assessment Scale and Penetration-Aspiration Scale. Data from clinical bedside examination and social information were collated to describe the impact of dysphagia in HD. Repeated VFSS data were available for seven individuals. Results: Swallowing was characterized by lingual dysfunction, reduced soft palate elevation, delayed pharyngeal swallow initiation, and inability to clear matter from the pharynx. Two-thirds of cases presented with compromised airway protection with both liquid and solid consistencies. Tachyphagia and difficulty self-feeding were common. Dysphagia correlated with disease severity and duration. Longitudinal analysis revealed a mixed pattern of progression with some individuals presenting with worsening dysphagia whilst others appeared to remain stable or improved in function. Conclusions: Dysphagia in HD is exacerbated by difficulties with self-feeding and monitoring feeding rate. Burden of pathology relates to pharyngeal swallow initiation and penetration and aspiration of fluid. Dysphagia did not appear to worsen in a systematic way in a subset of participants. Show more

Keywords: Swallowing, deglutition disorders, videofluoroscopy, trinucleotide expansion, neurodegeneration, speech

DOI: 10.3233/JHD-190390

Citation: Journal of Huntington's Disease, vol. 9, no. 2, pp. 163-171, 2020

Authors: McGarry, Andrew | Auinger, Peggy | Kieburtz, Karl | Geva, Michal | Mehra, Munish | Abler, Victor | Grachev, Igor D. | Gordon, Mark Forrest | Savola, Juha-Matti | Gandhi, Sanjay | Papapetropoulos, Spyridon | Hayden, Michael

Article Type: Research Article

Abstract: Background: Open-HART was an open-label extension of HART, a randomized, double-blind, placebo-controlled study of pridopidine in Huntington disease (HD). Previously, we reported safety and exploratory efficacy data after 36 months of treatment with pridopidine 45 mg twice daily. In the interim, emerging data suggests pridopidine may have neuroprotective effects mediated by sigma-1 receptor agonism. Objective: To report additional safety and exploratory efficacy data for continued open-label use of 45 mg BID pridopidine at 48 and 60 months. Methods: Patients in Open-HART were followed up to or greater than 60 months. Adverse events, concomitant medications, vital signs, laboratory values, …and ECG data were monitored. Rates of decline in total functional capacity (TFC) and total motor score (TMS) over 60 months were evaluated in an exploratory analysis and compared between Open-HART and placebo recipients from the 2CARE trial. To account for missing data, sensitivity analyses were performed. Results: Of the original Open-HART baseline cohort (N = 118), 40 remained in the study at 48 months and 33 at 60 months. Pridopidine remained safe and well tolerated over the 60-month interval. TFC and TMS at 48 and 60 months remained stable, showing less decline at these timepoints compared to historical placebo controls from the 2CARE trial. TFC differences at 48 and 60 months observed remained nominally significant after sensitivity analysis. Conclusion: The 45 mg BID pridopidine dosage remained safe and tolerable over 60 months. Exploratory analyses show TFC and TMS stability at 48 and 60 months, in contrast to placebo historical controls from the 2CARE trial. Results are consistent with data reported from the recent Phase 2 PRIDE-HD trial showing less functional decline in the pridopidine 45 mg BID treated group at 52 weeks. Show more

Keywords: Huntington disease, clinical trial, pridopidine, sigma-1-receptor

DOI: 10.3233/JHD-190393

Citation: Journal of Huntington's Disease, vol. 9, no. 2, pp. 173-184, 2020

Authors: Rodrigues, Filipe B. | Wild, Edward J.

Article Type: Other

Abstract: In this edition of the Huntington’s Disease Clinical Trials Corner we expand on the UniQure AMT-130 and on the Neurocrine Biosciences KINECT-HD trials, and list all currently registered and ongoing clinical trials in Huntington’s disease.

Keywords: Huntington disease, clinical trials

DOI: 10.3233/JHD-200002

Citation: Journal of Huntington's Disease, vol. 9, no. 2, pp. 185-197, 2020

Article Type: Other

DOI: 10.3233/JHD-209001

Citation: Journal of Huntington's Disease, vol. 9, no. 2, pp. 199-199, 2020