Journal of Huntington's Disease - Volume 8, issue 3

Authors: Brás, Inês Caldeira | König, Annekatrin | Outeiro, Tiago Fleming

Article Type: Review Article

Abstract: Glycation is the non-enzymatic reaction between reactive dicarbonyls and amino groups, and gives rise to a variety of different reaction products known as advanced glycation end products (AGEs). Accumulation of AGEs on proteins is inevitable, and is associated with the aging process. Importantly, glycation is highly relevant in diabetic patients that experience periods of hyperglycemia. AGEs also play an important role in neurodegenerative diseases including Alzheimer’s (AD) and Parkinson’s disease (PD). Huntington’s disease (HD) is a hereditary neurodegenerative disease caused by an expansion of a CAG repeat in the huntingtin gene. The resulting expanded polyglutamine stretch in the huntingtin (HTT) …protein induces its misfolding and aggregation, leading to neuronal dysfunction and death. HD patients exhibit chorea and psychiatric disturbances, along with abnormalities in glucose and energy homeostasis. Interestingly, an increased prevalence of diabetes mellitus has been reported in HD and in other CAG triplet repeat disorders. However, the mechanisms underlying the connection between glycation and HD progression remain unclear. In this review, we explore the possible connection between glycation and proteostasis imbalances in HD, and posit that it may contribute to disease progression, possibly by accelerating protein aggregation and deposition. Finally, we review therapeutic interventions that might be able to alleviate the negative impact of glycation in HD. Show more

Keywords: Huntington’s disease, huntingtin, glycation, advanced glycation end products, diabetes mellitus

DOI: 10.3233/JHD-190366

Citation: Journal of Huntington's Disease, vol. 8, no. 3, pp. 245-256, 2019

Authors: Mathkar, Pranav P. | Suresh, Divya | Dunn, James | Tom, Colton M. | Mattis, Virginia B.

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is an inherited neurodegenerative disease and is characterized by atrophy of certain regions of the brain in a progressive manner. HD patients experience behavioral changes and uncontrolled movements which can be primarily attributed to the atrophy of striatal neurons. Previous publications describe the models of the HD striatum using induced pluripotent stem cells (iPSCs) derived from HD patients with a juvenile onset (JHD). In this model, the JHD iPSC-derived striatal cultures had altered neurodevelopment and contained a high number of nestin expressing progenitor cells at 42 days of differentiation. Objective: To further characterize the …altered neurodevelopmental phenotype and evaluate potential phenotypic reversal. Methods: Differentiation of human iPSCs towards striatal fate and characterization by means of immunocytochemistry and stereological quantification. Results: Here this study demonstrates a distinct delay in the differentiation of the JHD neural progenitor population. However, reduction of the JHD aberrant progenitor populations can be accomplished either by targeting the canonical Notch signaling pathway or by treatment with HTT antisense oligonucleotides (ASOs). Conclusions: In summary, this data is postulated to reflect a potential overall developmental delay in JHD. Show more

Keywords: iPSC, Huntington’s disease, neurodegenerative disease, huntingtin, nestin

DOI: 10.3233/JHD-180333

Citation: Journal of Huntington's Disease, vol. 8, no. 3, pp. 257-269, 2019

Authors: Post, Joakim Iver | Leergaard, Trygve B. | Ratz, Veronika | Walaas, S. Ivar | von Hörsten, Stephan | Nissen-Meyer, Lise Sofie H.

Article Type: Research Article

Abstract: Background: The intracellular ion channel type 1 inositol 1,4,5-trisphosphate receptor (IP3 R1) releases Ca2+ from the endoplasmic reticulum upon stimulation with IP3 . Perturbation of IP3 R1 has been implicated in the development of several neurodegenerative disorders, including Huntington disease (HD). Objective: To elucidate the putative role of IP3 R1 phosphorylation in HD, we investigated IP3 R1 levels and protein phosphorylation state in the striatum, hippocampus and cerebellum of four murine HD models. Methods: Quantitative immunoblotting with antibodies to IP3 R1 protein and its phosphorylated serines 1589 and 1755 was applied to brain homogenates from …R6/1 mice to study early-onset aggressive HD. To determine if IP3 R1 changes precede overt pathology, we immunostained tissues from the regions of interest and several control regions for IP3 R1 in tgHDCAG51n rats and BACHD and zQ175DNKI mice, all recognized models for late-onset HD. Results: R6/1 mice had reduced total IP3 R1 immunoreactivity, variably reduced serine1755-phosphorylation in all regions investigated, and reduced serine1589-phosphorylation in cerebellum. IP3 R1 levels were decreased relative to cell-specific marker proteins. In tgHDCAG51n rats we found reduced IP3 R1 levels in the cerebellum, but otherwise unchanged IP3 R1 phosphorylation and protein levels. In BACHD and zQ175DNKI mice only age-dependent decline of IP3 R1 was observed. Conclusion: The level and phosphorylation of IP3 R1 is reduced to a variable degree in the different HD models relative to control, indicating that earlier findings in more aggressive exon 1-truncated HD models may not be replicated in models with higher construct validity. Further analysis of possible coupling of reduced IP3 R1 levels with development of neuropathological responses and cell-specific degeneration is warranted. Show more

Keywords: Cerebellum, Huntington disease, IP3 receptor, neurodegeneration, phosphorylation, transgenic model

DOI: 10.3233/JHD-180301

Citation: Journal of Huntington's Disease, vol. 8, no. 3, pp. 271-289, 2019

Authors: Adrissi, Jennifer | Nadkarni, Neil A. | Gausche, Eric | Bega, Danny

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is a progressive neurodegenerative disease characterized by involuntary movements and neuropsychiatric decline. With suicide rates five times higher in patients with HD compared to the general population, there is a need for further research into the management of affective symptoms in these patients. Electroconvulsive therapy (ECT) has been long used as a treatment for severe or medication-refractory mood disorders and catatonia. There are some case studies demonstrating ECT’s positive effect on depression and agitation in HD, but the data is limited. Objective: In this single site case series, we review ECT use for four …HD patients with medication-refractory depression and/or psychosis to better assess the utility of ECT in this population. We also compile and review the existing literature on the topic. Methods: A single-center retrospective case series was conducted reviewing the indications, outcomes, and regimen of ECT treatments. Literature review was conducted via PubMed. Results: Four patients received ECT treatment during an inpatient hospitalization with three continuing maintenance therapy as an outpatient. All four had improvements in depression, agitation, and suicidal ideation leading to successful hospital discharge. One of the four patients also demonstrated subjective improvement in cognitive and motor symptoms after ECT initiation. Nineteen reported cases were identified through the literature review and are summarized. Conclusions: This case series adds to the existing literature demonstrating the successful use of ECT for psychiatric symptoms in HD. Larger scale studies are warranted to further investigate the specific role and protocol for the use of ECT in the management of refractory depression and psychosis in this population. Show more

Keywords: Electroconvulsive therapy, Huntington’s disease, depression, mood disorders, psychotic disorders

DOI: 10.3233/JHD-190361

Citation: Journal of Huntington's Disease, vol. 8, no. 3, pp. 291-300, 2019

Authors: Yomtoob, Jacob | Yeh, Chen | Bega, Danny

Article Type: Research Article

Abstract: Background: Prior Huntington’s disease (HD) studies suggest ancillary services improve motor symptoms, cognition, mood, and quality of life but frequency of use and clinicalcharacteristics are unclear. Objective: Describe ancillary service utilization in a cohort of individuals with HD and determine which participant characteristics are associated with ancillary service utilization. Methods: Retrospective cross-sectional analysis of Enroll-HD database. Participants were grouped by therapy: physical and/or occupational (PT/OT), psychotherapy and/or counseling (PC), speech and/or swallowing (ST). We performed bivariate comparisons analysis of demographic and disease characteristics between those with/without each therapy and to analyze one-year mean change in assessment …scores. Results: Of 4751 participants, 1537 (32.35%) utilized therapies (11.82% PT/OT, 5.33% PC, 3.01% ST, 1.98% all three, 10.21% two therapies). PT/OT participants had worse motor and functional scores: mean UHDRS motor score (41.17 vs. 38.05, p  = 0.002), median total functional capacity score (TFC) (8.00 vs. 9.00, p  < 0.001). PC participants had worse mood but better cognitive and functional scores: median depression score (7.00 vs. 2.00, p  < 0.001), median MMSE (28.00 vs. 26.00, p  < 0.001), median TFC (10.00 vs. 8.00, p  < 0.001). ST participants had more dysarthria, and worse cognitive and functional scores: dysarthria (32.2% vs. 20.1% p  < 0.001), mean correct Symbol Digit Modality Test (16.79 vs. 23.27, p  < 0.001), median TFC (6.00 vs. 9.00, p  < 0.001). Over one year, PC participants’ depression scores improved compared to untreated (– 1.24 vs. – 0.11, p  = 0.040). ST participants’ depression scores worsened (1.14 vs. – 0.23, p  = 0.044). Mean change in TFC was not significant for any therapies. Conclusions: Only 32% of Enroll-HD site participants received ancillary services. Use correlated with expected clinical characteristics, though impact of use remains unclear. Show more

Keywords: Ancillary services, counseling, enroll-hd, Huntington’s disease, occupational, physical, psychotherapy, speech, swallow, therapy

DOI: 10.3233/JHD-190349

Citation: Journal of Huntington's Disease, vol. 8, no. 3, pp. 301-310, 2019

Authors: Matheis, Tamara | Evinger, Craig | Schubert, Robin | Mazzola, Steven | Fels, Michaela | Kemper, Nicole | Reilmann, Ralf | Muratori, Lisa

Article Type: Research Article

Abstract: Background: The ability of healthy individuals to detect biological motion by using a small number of moving points is well established in animals and humans. Perception of human movements may depend on internal models that drive self-generated movements and influence motion discrimination (Reed CL et al. 1995 and 2007). As a person’s motor repertoire deteriorates, the accuracy of these models may also decrease. Objective: Determine if people with symptomatic Huntington’s disease (HD) have difficulty perceiving movements. Methods: In this study point-light displays were created with a Vicon Motion Capture System by recording one individual with (impaired) …and one individual without (healthy) Parkinson’s disease using a 13 joint marker set. Participants were asked to distinguish between three movements and determine if the movement was impaired or healthy. The ability of participants with and without HD to distinguish movement patterns and the time to perception were recorded. Results: Analyses found participants with HD had a decreased ability to correctly detect movements and point-light image type. The stair climbing motion showed the largest effect as participants with HD had more difficulty correctly identifying both the movement and whether it was impaired or healthy. In addition, the participants without HD showed an improvement as trials progressed which could not be observed in the HD cohort. Conclusions: As people with symptomatic HD have difficulty perceiving movements further investigations using point-light displays should be done to determine if these impairments might serve as an easily administered, non-invasive marker of disease state. Show more

Keywords: Point-light display, biomarker, visual perception, neurodegenerative disease

DOI: 10.3233/JHD-180337

Citation: Journal of Huntington's Disease, vol. 8, no. 3, pp. 311-321, 2019

Authors: Li, Fan | Li, Kan | Li, Cai | Luo, Sheng | PREDICT-HD and ENROLL-HD Investigators of the Huntington Study Group

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) has gradually become a public health threat, and there is a growing interest in developing prognostic models to predict the time for HD diagnosis. Objective: This study aims to develop a novel prognostic model that leverages multiple longitudinal biomarkers to inform the risk of HD. Methods: The multivariate functional principal component analysis was used to summarize the essential information from multiple longitudinal markers and to obtain a set of prognostic scores. The prognostic scores were used as predictors in a Cox model to predict the right-censored time to diagnosis. We used cross-validation …to determine the best model in PREDICT-HD (n  = 1,039) and ENROLL-HD (n  = 1,776); external validation was carried out in ENROLL-HD. Results: We considered six commonly measured longitudinal biomarkers in PREDICT-HD and ENROLL-HD (Total Motor Score, Symbol Digit Modalities Test, Stroop Word Test, Stroop Color Test, Stroop Interference Test, and Total Functional Capacity). The prognostic model utilizing these longitudinal biomarkers significantly improved the predictive performance over the model with baseline biomarker information. A new prognostic index was computed using the proposed model, and can be dynamically updated over time as new biomarker measurements become available. Conclusion: Longitudinal measurements of commonly measured clinical biomarkers substantially improve the risk prediction of Huntington’s disease diagnosis. Calculation of the prognostic index informs the patient’s risk category and facilitates patient selection in future clinical trials. Show more

Keywords: Cognitive disorders, cross validation, functional principal component analysis, Huntington’s disease, motor diagnosis, risk prediction

DOI: 10.3233/JHD-190345

Citation: Journal of Huntington's Disease, vol. 8, no. 3, pp. 323-332, 2019

Authors: van der Plas, Ellen | Schubert, Robin | Reilmann, Ralf | Nopoulos, Peggy C.

Article Type: Research Article

Abstract: Q-Motor is utilized across various clinical trials in adults with Huntington’s disease (HD) to provide quantitative, reliable assessments of motor abilities. With gene-knockdown therapies entering the clinic, development of preventative therapies for pediatric carriers of the HD mutation seems imminent. It is currently unclear if Q-Motor is useful for tracking changes in motor abilities in pediatric HD patients or at-risk youth, as most assessments have never been administered in children. We demonstrate the feasibility of administering Q-Motor tasks in a sample of children recruited from the community, and we show that Q-Motor is sensitive to age-related changes in motor abilities.

Keywords: Q-Motor, Huntington’s disease, development, endpoint, motor, children, adolescents

DOI: 10.3233/JHD-190353

Citation: Journal of Huntington's Disease, vol. 8, no. 3, pp. 333-338, 2019

Authors: Nasr, Shahin | Rosas, Herminia D.

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is a genetic disorder known for affecting motor control. Despite evidence for the impact of HD on visual cortico-striatal loops, evidence for impaired visual perception in early symptomatic HD patients is limited; much less is known about what happens during the HD prodrome. Objective: The goals of this study were to evaluate perceptual processing in motor pre-manifest HD gene-carriers (Pre-HDs) during a visual mental rotation task. Methods: To achieve this goal, 79 participants including 24 Pre-HD participants and 55 healthy matched controls were scanned using functional MRI as they performed a mental …rotation task. Another group of 36 subjects including 15 pre-HDs and 21 healthy age/gender matched controls participated in a control behavioral test of judgment of line orientation outside the scanner. Results: We found that, although Pre-HDs (in this stage of disease) did not demonstrate slower response times, their response accuracy was lower than controls. On the fMRI task, controls showed a significant decrease in activity in the occipito-temporal (OT) visual network and increase in activity in the caudo-fronto-parietal (CFP) network with mental rotation load. Interestingly, the amount of mental rotation-related activity decrease in the OT network was reduced in Pre-HDs compared to controls while, the level of CFP response remained unchanged between the two groups. Comparing the link between the evoked BOLD activity within these networks and response accuracy (i.e., behavior), we found that the models fit to data from controls were less accurate in predicting response accuracy of Pre-HDs. Conclusion: These findings provide some of the earliest functional evidence of impaired visual processing and altered neural processing underlying visual perceptual decision making during the HD prodrome. Show more

Keywords: Mental rotation, Pre-HD, visual system, functional MRI

DOI: 10.3233/JHD-190348

Citation: Journal of Huntington's Disease, vol. 8, no. 3, pp. 339-356, 2019

Authors: Quarrell, Oliver W. | Delatycki, Martin B. | Clarke, Angus J. | Lahiri, Nayana | Craufurd, David | Miedzybrodzka, Zosia | MacLeod, Rhona | Renwick, Pamela | Tomlinson, Charlotte

Article Type: Letter

DOI: 10.3233/JHD-190360

Citation: Journal of Huntington's Disease, vol. 8, no. 3, pp. 357-359, 2019