Huntington’s Disease

Huntington’s disease (HD) research is aimed at understanding the root cause of the disorder, for the thrill of uncovering new biology, and for the serious purpose of finding effective therapeutic agents. Molecular genetics has revealed the disease trigger, an inherited unstable CAG expansion in a novel 4p16.3 gene (HD), that lengthens a polyglutamine segment in huntingtin. Now studies with HD patients and model systems that are genetic HD replicas are homing in on the trigger mechanism and the first formative steps that cast HD as a distinct clinical entity. At the same time, assays at the biochemical, cellular, and whole organism levels are starting to yield potential disease modifying genes and candidate drugs. These can be prioritized by testing in a panel of genetic and phenotypic HD mouse models to yield analytical tools for dissecting the early and late stages of the disease process and to maximize the chance of success in trials with HD patients.     

Curcumin Nanoparticles Attenuate Neurochemical and Neurobehavioral Deficits in Experimental Model of Huntington’s Disease

Till date, an exact causative pathway responsible for neurodegeneration in Huntington’s disease (HD) remains elusive; however, mitochondrial dysfunction appears to play an important role in HD pathogenesis. Therefore, strategies to attenuate mitochondrial impairments could provide a potential therapeutic intervention. In the present study, we used curcumin encapsulated solid lipid nanoparticles (C-SLNs) to ameliorate 3-nitropropionic acid (3-NP)-induced HD in rats. Results of MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) assay and succinate dehydrogenase (SDH) staining of striatum revealed a marked decrease in Complex II activity. However, C-SLN-treated animals showed significant increase in the activity of mitochondrial complexes and cytochrome levels. C-SLNs also restored the glutathione levels and superoxide dismutase activity. Moreover, significant reduction in mitochondrial swelling, lipid peroxidation, protein carbonyls and reactive oxygen species was observed in rats treated with C-SLNs. Quantitative PCR and Western blot results revealed the activation of nuclear factor-erythroid 2 antioxidant pathway after C-SLNs administration in 3-NP-treated animals. In addition, C-SLN-treated rats showed significant improvement in neuromotor coordination when compared with 3-NP-treated rats. Thus, the results of this study suggest that C-SLNs administration might be a promising therapeutic intervention to ameliorate mitochondrial dysfunctions in HD.     

Treatment of Huntington’s Disease

Huntington’s disease (HD) is a dominantly inherited progressive neurological disease characterized by chorea, an involuntary brief movement that tends to flow between body regions. HD is typically diagnosed based on clinical findings in the setting of a family history and may be confirmed with genetic testing. Predictive testing is available to family members at risk, but only experienced clinicians should perform the counseling and testing. Multiple areas of the brain degenerate, mainly involving the neurotransmitters dopamine, glutamate, and γ-aminobutyric acid. Although pharmacotherapies theoretically target these neurotransmitters, few well-conducted trials for symptomatic interventions have yielded positive results and current treatments have focused on the motor aspects of HD. Tetrabenazine is a dopamine-depleting agent that may be one of the more effective agents for reducing chorea, although it has a risk of potentially serious adverse effects. Some newer neuroleptic agents, such as olanzapine and aripiprazole, may have adequate efficacy with a more favorable adverse effect profile than older neuroleptic agents for treating chorea and psychosis. There are no current treatments to change the course of HD, but education and symptomatic therapies can be effective tools for clinicians to use with patients and families affected by HD.     

Huntington’s Disease and Mitochondria

Huntington’s disease (HD) as an inherited neurodegenerative disorder leads to neuronal loss in striatum. Progressive motor dysfunction, cognitive decline, and psychiatric disturbance are the main clinical symptoms of the HD. This disease is caused by expansion of the CAG repeats in exon 1 of the huntingtin which encodes Huntingtin protein (Htt). Various cellular and molecular events play role in the pathology of HD. Mitochondria as important organelles play crucial roles in the most of neurodegenerative disorders like HD. Critical roles of the mitochondria in neurons are ATP generation, Ca²⁺ buffering, ROS generation, and antioxidant activity. Neurons as high-demand energy cells closely related to function, maintenance, and dynamic of mitochondria. In the most neurological disorders, mitochondrial activities and dynamic are disrupted which associate with high ROS level, low ATP generation, and apoptosis. Accumulation of mutant huntingtin (mHtt) during this disease may evoke mitochondrial dysfunction. Here, we review recent findings to support this hypothesis that mHtt could cause mitochondrial defects. In addition, by focusing normal huntingtin functions in neurons, we purpose mitochondria and Huntingtin association in normal condition. Moreover, mHtt affects various cellular signaling which ends up to mitochondrial biogenesis. So, it could be a potential candidate to decline ATP level in HD. We conclude how mitochondrial biogenesis plays a central role in the neuronal survival and activity and how mHtt affects mitochondrial trafficking, maintenance, integrity, function, dynamics, and hemostasis and makes neurons vulnerable to degeneration in HD.     

Astrocytes and Huntington’s Disease

Inthis Viewpoint, we summarize and discuss the recent serendipitousdiscovery of an astrocyte Kir4.1 potassium channel dysfunction intwo mouse models of Huntington’s disease (HD). Restorationof Kir4.1 channels within astrocytes in vivo attenuated neuronal dysfunction,some aspects of motor dysfunction and increased survival time in aHD mouse model. Overall, the data show that aspects of altered neuronalexcitability associated with HD may be secondary to changes in astrocyte-mediatedK⁺ homeostasis, thereby revealing a new striatal neuralmicrocircuit mechanism in HD, and Kir4.1 channels and astrocytes aspotential therapeutic targets for drug development.     

A Case of Unilateral Neglect in Huntington’s Disease

Unilateral neglect, an attentional deficit in detecting and acting on information coming from one side of space, is a relatively common consequence of right hemisphere stroke. Although neglect has been observed following damage to a variety of brain structures, to date no reports exist of neglect phenomena arising from Huntington’s Disease (HD). However, reports in the animal and human literature suggest that neglect is possible following damage to a primary site for Huntington’s pathology, the basal ganglia. Here we present a patient (BG) with genetically proven HD who, in the context of the mild intellectual, executive and attentional impairments associated with the disorder, showed a remarkably severe and stable neglect for left space. MRI and electrophysiological results make it unlikely that the spatial bias could be accounted for by basic sensory loss. In addition, behavioural investigation indicated that, although BG’s neglect operated in a very striking manner along body-centred co-ordinates (missing almost all information presented to her left), more general limitations in visual attention were apparent to the left-side of information presented entirely to the right of the body midline. Further evidence is presented showing that the neglect was manifest on tactile and auditory tasks as well as those presented in the visual domain. The presence of neglect in HD in this case is novel and somewhat puzzling, particularly as flourodeoyglucose positron emission tomography revealed bilateral caudate hypoperfusion. Reducing the statistical threshold on this analysis revealed a potential frontal hypometabolism that was more marked in the right than left hemisphere. However, as this was only apparent at a threshold below that normally considered acceptable (due to the resulting number of false positives), this possible account of the neglect must be viewed very cautiously.     

Therapy in Huntington’s Disease: Where Are We?

As of 2012, almost 20 years after the discovery of the causative gene, clinical research has yet to find a disease-modifying treatment for Huntington's disease. However, both pharmacologic and nonpharmacologic therapies are available for many of the common symptoms of the disease. Recent studies of gene-positive patients in the prodromal, not clinically diagnosable, stages of the disease, are changing our perception of when the process of neurodegeneration begins. Once disease-modifying therapies become available, the approach to the diagnosis of Huntington's disease will likely shift from an examination-based clinical diagnosis, to one that includes a more complex combination of imaging, examination, and biomarker analysis.     

Huntington’s Disease—Update on Treatments

Huntington’s disease (HD) is an autosomal dominantly inherited neurodegenerative disease characterized by progressive motor, behavioral, and cognitive decline, ending in death. Despite the discovery of the underlying genetic mutation more than 20 years ago, treatment remains focused on symptomatic management. Chorea, the most recognizable symptom, responds to medication that reduces dopaminergic neurotransmission. Psychiatric symptoms such as depression and anxiety may also respond well to symptomatic therapies. Unfortunately, many other symptoms do not respond to current treatments. Furthermore, high-quality evidence for treatment of HD in general remains limited. To date, there has been minimal success with identifying a disease-modifying therapy based upon molecular models. However, one of the emerging gene silencing techniques may provide a breakthrough in treating this devastating disease.     

Dalbiez’s Contribution to Psychoanalysis

Objective: This study examined how inner perceptions that develop in the aftermath of exposure to trauma attenuate the association between posttraumatic symptoms across time and what the reciprocal relations between inner perceptions of trauma and posttraumatic symptoms are. Method: The present article is based on two studies. The data in Study 1 are drawn from three waves of a longitudinal study of community-dwelling midlife adults and older adults residing in the south of Israel. In Wave 1, 339 participants were interviewed (mean age = 65.44, SD = 9.77). Of these participants, 170 and 132, respectively, participated in Waves 2 (one year later) and 3 (two years later). Posttraumatic stress symptoms were self-reported in all three waves. Inner perceptions of trauma were assessed with the Subjective Traumatic Outlook scale (STO) and Centrality of Event Scale (CES), administered at Wave 3. Study 2 is drawn from two waves of research of young adults. Wave 1 included 138 participants (mean age = 32.01, SD = 10.57) from a convenience sample. At Wave 2, 128 participants were interviewed again a month later. Participants reported their level of posttraumatic stress symptoms and completed the STO and the CES in both waves. Results: In Study 1, analyses showed stronger associations between posttraumatic symptoms across waves among those who reported higher subjective traumatic outlook and higher centrality of events. In Study 2, significant reciprocal relationships between PTSD and STO were found, but whereas the W1 PTSD–W2 CES path was significant, the W1 CES–W2 PTSD path was not. Conclusions: The findings emphasize that overintegration and especially disintegration of the pretraumatic identity with traumatic experiences are associated with the deleterious effects of long-lasting exposure to traumatic events.     

A Critical Review of White Matter Changes in Huntington’s Disease

Huntington’s disease is a genetic neurodegenerative disorder. White matter alterations have recently been identified as a relevant pathophysiological feature of Huntington’s disease, but their etiology and role in disease pathogenesis and progression remain unclear. Increasing evidence suggests that white matter changes in this disorder are attributed to alterations in myelin-associated biological processes. This review first discusses evidence from neurochemical studies lending support to the demyelination hypothesis of Huntington’s disease, demonstrating aberrant myelination and changes in oligodendrocytes in the Huntington’s brain. Next, evidence from neuroimaging studies is reviewed, the limitations of the described methodologies are discussed, and suggested interpretations of findings from published studies are challenged. Although our understanding of Huntington’s associated pathological changes in the brain will increasingly rely on neuroimaging techniques, the shortcomings of these methodologies must not be forgotten. Advances in magnetic resonance imaging techniques and tissue modeling will enable a better in vivo, longitudinal characterization of the biological properties of white matter microstructure. This in turn will facilitate identification of disease-related biomarkers and the specification of outcome measures in clinical trials. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.     

Neuroinflammation in Huntington’s disease

Huntington’s disease (HD) is a monogenic neurodegenerative disease characterized by abnormal motor movements, personality changes and early death. In contrast to other neurodegenerative diseases, very little is known about the role of neuroinflammation in HD. While the current data clearly demonstrate the existence of inflammatory processes in HD pathophysiology, the question of whether neuroinflammation is purely reactive or might actively participate in disease pathogenesis is currently a matter of ongoing research and debate. This review will try to shed some light on the current state of research in this area and provide an outlook on potential future developments.     

Statistical Approaches to Longitudinal Data Analysis in Neurodegenerative Diseases: Huntington’s Disease as a Model

Understanding the overall progression of neurodegenerative diseases is critical to the timing of therapeutic interventions and design of effective clinical trials. Disease progression can be assessed with longitudinal study designs in which outcomes are measured repeatedly over time and are assessed with respect to risk factors, either measured repeatedly or at baseline. Longitudinal data allows researchers to assess temporal disease aspects, but the analysis is complicated by complex correlation structures, irregularly spaced visits, missing data, and mixtures of time-varying and static covariate effects. We review modern statistical methods designed for these challenges. Among all methods, the mixed effect model most flexibly accommodates the challenges and is preferred by the FDA for observational and clinical studies. Examples from Huntington’s disease studies are used for clarification, but the methods apply to neurodegenerative diseases in general, particularly as the identification of prodromal forms of neurodegenerative disease through sensitive biomarkers is increasing.     

Cerebellar and Motor Cortical Transcranial Stimulation Decrease Levodopa-Induced Dyskinesias in Parkinson’s Disease

Transcranial direct current stimulation (tDCS) is a non-invasive technique for inducing prolonged functional changes in the human cerebral cortex. This simple and safe neurostimulation technique for modulating motor functions in Parkinson’s disease could extend treatment option for patients with movement disorders. We assessed whether tDCS applied daily over the cerebellum (cerebellar tDCS) and motor cortex (M1-tDCS) improves motor and cognitive symptoms and levodopa-induced dyskinesias in patients with Parkinson’s disease (PD). Nine patients (aged 60–85 years; four women; Hoehn & Yahr scale score 2–3) diagnosed as having idiopathic PD were recruited. To evaluate how tDCS (cerebellar tDCS or M1-tDCS) affects motor and cognitive function in PD, we delivered bilateral anodal (2 mA, 20 min, five consecutive days) and sham tDCS, in random order, in three separate experimental sessions held at least 1 month apart. In each session, as outcome variables, patients underwent the Unified Parkinson’s Disease Rating Scale (UPDRS III and IV) and cognitive testing before treatment (baseline), when treatment ended on day 5 (T1), 1 week later (T2), and then 4 weeks later (T3), at the same time each day. After patients received anodal cerebellar tDCS and M1-tDCS for five days, the UPDRS IV (dyskinesias section) improved (p?<?0.001). Conversely, sham tDCS, cerebellar tDCS, and M1-tDCS left the other variables studied unchanged (p?>?0.05). Despite the small sample size, our preliminary results show that anodal tDCS applied for five consecutive days over the motor cortical areas and cerebellum improves parkinsonian patients’ levodopa-induced dyskinesias.     

Cell therapy in Huntington’s disease

Huntington’s disease is an autosomal dominant genetic disease, which results in progressive neuronal degeneration in the neostriatum and neocortex, and associated functional impairments in motor, cognitive, and psychiatric domains. Although the genetic mutation is identified, involving an abnormal CAG expansion within thehtt gene on chromosome 4, the mechanism by which this leads to neuronal cell death and the question of why striatal neurones are targeted both remain unknown. Thus, in addition to the search for molecular and genetic strategies to inhibit development of the disease, we still need to identify effective strategies for cellular repair in affected individuals. Aspects of the human neuropathology can be well modeled by excitotoxic or metabolic lesions in experimental animals, and in transgenic mice carrying thehtt mutation, providing the basis for testing alternative therapeutic strategies. The rationale and efficacy of alternative cell therapies are reviewed, including transplantation repair with embryonic striatal tissues, expansion and differentiation of striatal-like cells from stem cells, andin vivo andex vivo gene therapy for delivery of neuroprotective growth factor molecules. Pilot and experimental clinical trials of several approaches are now also underway, and the alternative strategies are compared.     

Drug-induced hyperthermia in Huntington’s disease

Abstract. Until now, only three patients with Huntingtons disease (HD) and a neuroleptic malignant syndrome (NMS) have been reported in the literature. We describe four cases with advanced stage Huntingtons disease who within a period of one year developed drug-induced hyperthermia, either the neuroleptic malignant syndrome, or the serotonin syndrome. Possible contributing factors that may have been specific for HD patients could be identified and included advanced neurological disease with severe illness, occurrence in summer, with possible infectious disease, dehydration, and pre-existing extra-pyramidal signs that may mask incipient NMS/serotonin syndrome. Measures to avoid these potentially lifethreatening conditions are discussed.     

Sensory processing in Huntington’s disease

Objective

An intriguing electrophysiological feature of patients with Huntington’s disease (HD) is the delayed latency and decreased amplitude of somatosensory long-latency evoked potentials (LLeps). We investigated whether such dysfunction was associated with delayed conscious perception of the sensory stimulus.

Correction of Huntington’s Disease Phenotype by Genistein-Induced Autophagy in the Cellular Model

Huntington’s disease (HD) is a monogenic disorder, caused by mutations in the HTT gene which result in expansion of CAG triplets. The product of the mutated gene is misfolded huntingtin protein that forms aggregates leading to impairment of neuronal function, neurodegeneration, motor abnormalities and cognitive deficits. No effective cure is currently available for HD. Here we studied effects of genistein (trihydroxyisoflavone) on a HD cellular model consisting of HEK-293 cells transfected with a plasmid bearing mutated HTT gene. Both level of mutated huntingtin and number of aggregates were significantly decreased in genistein-treated HD cell model. This led to increased viability of the cells. Autophagy was up-regulated while inhibition of lysosomal functions by chloroquine impaired the genistein-mediated degradation of the mutated huntingtin aggregates. Hence, we conclude that through stimulating autophagy, genistein removes the major pathogenic factor of HD. Prolonged induction of autophagy was suspected previously to be risky for patients due to putative adverse effects; however, genistein has been demonstrated recently to be safe and suitable for long-term therapies even at doses as high as 150 mg/kg/day. Therefore, results presented in this report provide a basis for the use of genistein in further studies on development of the potential treatment of HD.