The Latest Articles on Huntington's Disease
Our staff editors continue to share exciting, interesting, and thought-provoking reading material in the recommended articles series.
This week, we would like to share several latest articles on Huntington's Disease.
Title: Nursing home residents with Huntington’s disease: Heterogeneity in characteristics and functioning
Authors: Marina R. Ekkel, Ruth B. Veenhuizen, Anouk M. van Loon, Marja F.I.A. Depla, Els M.L. Verschuur, Bregje D. Onwuteaka-Philipsen, Cees M.P.M. Hertogh
Type: Research Article
Abstract:
Background
In Huntington’s disease (HD), admission to a nursing home (NH) is required in advanced disease stages. To gain insight in care needs, more knowledge is needed on the functioning of this group.
Objective
Describing patient and disease characteristics, their functioning, and gender differences.
Methods
A cross-sectional descriptive design was used to collect data of 173 patients living in eight Dutch HD-specialized NHs. Data were collected on characteristics and functioning. We tested for gender differences.
Results
Mean age was 58.3 years and 49.7% were men. Activities of daily living and cognition varied from 46 to 49% mildly impaired to 22–23% severely impaired. Communication was severely impaired in 24%. Social functioning was low in 31% and high in 34%. A majority of patients used psychotropic medications (80.3%) and showed neuropsychiatric signs (74%). Women were on average more dependent in ADL (severely impaired 33.3% vs 12.8%), more often depressed (26.4% vs 11.6%), and prescribed antidepressant medications more often (64.4% vs 48.8%) than men.
Conclusions
The population of HD patients in NHs is heterogeneous in terms of patient and disease characteristics, and functioning. As a consequence, care needs are complex leading to implications for the required expertise of staff to provide adequate care and treatment.
Access this article: https://doi.org/10.1016/j.bandc.2023.106002
Title: Mitochondrial dysfunction and oxidative stress in Alzheimer’s disease, and Parkinson’s disease, Huntington’s disease and Amyotrophic Lateral Sclerosis -An updated review
Authors: Taha Alqahtani, Sharada L. Deore, Anjali A. Kide, Bhavana A. Shende, Ritika Sharma, Rita Dadarao Chakole, Lalita S. Nemade, Nikita Kishor Kale, Sudarshana Borah, Savita Shrikant Deokar, Ashok Behera, Divya Dhawal Bhandari, Nikita Gaikwad, Abul Kalam Azad, Arabinda Ghosh
Type: Review
Abstract:
Misfolded proteins in the central nervous system can induce oxidative damage, which can contribute to neurodegenerative diseases in the mitochondria. Neurodegenerative patients face early mitochondrial dysfunction, impacting energy utilization. Amyloid-ß and tau problems both have an effect on mitochondria, which leads to mitochondrial malfunction and, ultimately, the onset of Alzheimer's disease. Cellular oxygen interaction yields reactive oxygen species within mitochondria, initiating oxidative damage to mitochondrial constituents. Parkinson's disease, linked to oxidative stress, α-synuclein aggregation, and inflammation, results from reduced brain mitochondria activity. Mitochondrial dynamics profoundly influence cellular apoptosis via distinct causative mechanisms. The condition known as Huntington's disease is characterized by an expansion of polyglutamine, primarily impacting the cerebral cortex and striatum. Research has identified mitochondrial failure as an early pathogenic mechanism contributing to HD's selective neurodegeneration. The mitochondria are organelles that exhibit dynamism by undergoing fragmentation and fusion processes to attain optimal bioenergetic efficiency. They can also be transported along microtubules and regulate intracellular calcium homeostasis through their interaction with the endoplasmic reticulum. Additionally, the mitochondria produce free radicals. The functions of eukaryotic cells, particularly in neurons, have significantly deviated from the traditionally assigned role of cellular energy production. Most of them are impaired in HD, which may lead to neuronal dysfunction before symptoms manifest. This article summarises the most important changes in mitochondrial dynamics that come from neurodegenerative diseases including Alzheimer's, Parkinson's, Huntington's and Amyotrophic Lateral Sclerosis. Finally, we discussed about novel techniques that can potentially treat mitochondrial malfunction and oxidative stress in four most dominating neuro disorders.
Access this article: https://doi.org/10.1016/j.mito.2023.05.007
Title: Alterations of fractional anisotropy throughout cortico-basal ganglia gray matter in a macaque model of Huntington’s Disease
Authors: Alison R. Weiss, William A. Liguore, Kristin Brandon, Xiaojie Wang, Zheng Liu, Christopher D. Kroenke, Jodi L. McBride
Type: Research Article
Abstract:
We recently generated a nonhuman primate (NHP) model of the neurodegenerative disorder, Huntington's disease (HD), using adeno-associated viral vectors to express a fragment of mutant HTT protein throughout the cortico-basal ganglia circuit. Previous work by our group established that mHTT-treated NHPs exhibit progressive motor and cognitive phenotypes which are accompanied by mild volumetric reductions of cortical-basal ganglia structures and reduced fractional anisotropy (FA) in the white matter fiber pathways interconnecting these regions, mirroring findings observed in early-stage HD patients. Given the mild structural atrophy observed in cortical and sub-cortical gray matter regions characterized in this model using tensor-based morphometry, the current study sought to query potential microstructural alterations in the same gray matter regions using diffusion tensor imaging (DTI), to define early biomarkers of neurodegenerative processes in this model. Here, we report that mHTT-treated NHPs exhibit significant microstructural changes in several cortical and subcortical brain regions that comprise the cortico-basal ganglia circuit; with increased FA in the putamen and globus pallidus and decreased FA in the caudate nucleus and several cortical regions. DTI measures also correlated with motor and cognitive deficits such that animals with increased basal ganglia FA, and decreased cortical FA, had more severe motor and cognitive impairment. These data highlight the functional implications of microstructural changes in the cortico-basal ganglia circuit in early-stage HD.
Access this article: https://doi.org/10.1016/j.crneur.2023.100090
Title: Advances in stem cell and other therapies for Huntington’s disease: An update
Authors: LT Conner, B. Srinageshwar, JL Bakke, GL Dunbar, J. Rossignol
Type: Review
Abstract:
Huntington’s disease (HD) is a neurodegenerative disorder caused by an autosomal dominant mutation leading to an abnormal CAG repeat expansion. The result is the synthesis of a toxic misfolded protein, called the mutant huntingtin protein (mHTT). Most current treatments are palliative, but the latest research has expanded into multiple modalities, including stem cells, gene therapy, and even the use of 3D cell structures, called organoids. Stem cell research as a treatment for HD has included the use of various types of stem cells, such as mesenchymal stem cells, neural stem cells, embryonic stem cells, and even reprogrammed stem cells called induced pluripotent stem cells. The goal has been to develop stem cell transplant grafts that will replace the existing mutated neurons, as well as release existing trophic factors for neuronal support. Additionally, research in gene modification using CRISPR-Cas9, PRIME editing, and other forms of genetic modifications are continuing to evolve. Most recently, advancements in stem cell modeling have yielded 3D stem cell tissue models, called organoids. These organoids offer the unique opportunity to transplant a structured stem cell graft which, ideally, models normal human brain tissue more accurately. This manuscript summarizes the recent research in stem cells, genetic modifications, and organoids as a potential for treatment of HD.
Access this article: https://doi.org/10.1016/j.brainresbull.2023.110673
Title: Safety and efficacy of valbenazine for the treatment of chorea associated with Huntington's disease (KINECT-HD): a phase 3, randomised, double-blind, placebo-controlled trial
Authors: Prof Erin Furr Stimming MD, Daniel O Claassen MD, Elise Kayson MS, Jody Goldstein BS, Raja Mehanna MD, Hui Zhang PhD, Grace S Liang MD, Dietrich Haubenberger MD
Huntington Study Group KINECT-HD Collaborators*
Type: Research Article
Abstract:
Summary:
Background
Valbenazine is a highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor approved for treatment of tardive dyskinesia. To address the ongoing need for improved symptomatic treatments for individuals with Huntington's disease, valbenazine was evaluated for the treatment of chorea associated with Huntington's disease.
Methods
KINECT-HD (NCT04102579) was a phase 3, randomised, double-blind, placebo-controlled trial, performed in 46 Huntington Study Group sites in the USA and Canada. The study included adults with genetically confirmed Huntington's disease and chorea (Unified Huntington's Disease Rating Scale [UHDRS] Total Maximal Chorea [TMC] score of 8 or higher) who were randomly assigned (1:1) via an interactive web response system (with no stratification or minimisation) to oral placebo or valbenazine (≤80 mg, as tolerated) for 12 weeks of double-blinded treatment. The primary endpoint was a least-squares mean change in UHDRS TMC score from the screening and baseline period (based on the average of screening and baseline values for each participant) to the maintenance period (based on the average of week 10 and 12 values for each participant) in the full-analysis set using a mixed-effects model for repeated measures. Safety assessments included treatment-emergent adverse events, vital signs, electrocardiograms, laboratory tests, clinical tests for parkinsonism, and psychiatric assessments. The double-blind placebo-controlled period of KINECT-HD has been completed, and an open-label extension period is ongoing.
Findings
KINECT-HD was performed from Nov 13, 2019, to Oct 26, 2021. Of 128 randomly assigned participants, 125 were included in the full-analysis set (64 assigned to valbenazine, 61 assigned to placebo) and 127 were included in the safety-analysis set (64 assigned to valbenazine, 63 assigned to placebo). The full-analysis set included 68 women and 57 men. Least-squares mean changes from the screening and baseline period to the maintenance period in the UHDRS TMC score were –4·6 for valbenazine and –1·4 for placebo (least-squares mean difference –3·2, 95% CI –4·4 to –2·0; p<0·0001). The most commonly reported treatment-emergent adverse event was somnolence (ten [16%] with valbenazine, two [3%] with placebo). Serious treatment-emergent adverse events were reported in two participants in the placebo group (colon cancer and psychosis) and one participant in the valbenazine group (angioedema because of allergic reaction to shellfish). No clinically important ch anges in vital signs, electrocardiograms, or laboratory tests were found. No suicidal behaviour or worsening of suicidal ideation was reported in participants treated with valbenazine.
Interpretation
In individuals with Huntington's disease, valbenazine resulted in improvement in chorea compared with placebo and was well tolerated. Continued research is needed to confirm the long-term safety and effectiveness of this medication throughout the disease course in individuals with Huntington's disease-related chorea.
Funding
Neurocrine Biosciences.
Access this article: https://doi.org/10.1016/S1474-4422(23)00127-8
