Huntington's Disease Symptoms Research Articles

Cancer: From Wild-Type to Mutant Huntingtin.

Huntingtin (HTT) is a scaffold protein mostly known because it gives rise to the severe and incurable inherited neurological disorder Huntington’s disease (HD) when mutated. The Huntingtin gene (HTT) carries a polymorphic trinucleotide expansion of CAGs in exon 1 that ranges from 9 to 35 in the non-HD affected population. However, if it exceeds 35 CAG repeats, the altered protein is referred to as mutant HTT and leads to the development of HD. Given the wide spectrum of severe symptoms developed by HD individuals, wild-type and mutant HTT have been mostly studied in the context of this disorder. However, HTT expression is ubiquitous and several peripheral symptoms in HD have been described, suggesting that HTT is of importance, not only in the central nervous system (CNS), but also in peripheral organs. Accordingly, HTT and mutant HTT may interfere with non-brain-related diseases. Correlative studies have highlighted a decreased cancer incidence in the HD population and both wild-type and mutant HTT have been implicated in tumor progression. In this review, we describe the current evidence linking wild-type and mutant HTT to cancer and discuss how CAG polymorphism, HTT function, and partners may influence carcinogenesis and metastatic progression.

Huntington's disease: Neuropsychiatric manifestations of Huntington's disease.

Huntington's disease (HD) is a profoundly incapacitating, and ultimately fatal, neurodegenerative disease. HD is presently incurable, so the current goal is to allow affected individuals to live as well as possible with the illness, to maximise functional independence and quality of life for the person with HD, their carers and family members. This clinical update review focuses on the common neuropsychiatric manifestations in HD, and outlines and evaluates the various neuropsychiatric facets of HD, including the aetiology, symptoms and diagnosis. Neuropsychiatric symptoms can precede the classic motor clinical symptoms of HD (prodromal HD) by decades, and cause significant functional impairment. HD provides key insights and understanding into the organic psychiatric disorders, including contemporary clinical insights into the process of neurodegeneration and manifestation of neuropsychiatric symptoms.

Green tea infusion alleviates neurodegeneration induced by mutant Huntingtin in Drosophila

Objectives: Green tea infusion contains a complex mixture of polyphenolic compounds that were shown to provide health benefits. It was previously demonstrated that (-)-epigallocatechin-3-gallate, one of the major polyphenols present in green tea, has a suppressing effect on various aspects of pathogenesis in models of Huntington’s disease (HD), an inherited neurodegenerative disorder. In this study, we aimed to investigate, whether green tea infusion prepared as for human consumption has similar positive effects.Methods: We used a transgenic Drosophila model of HD to study the effects of green tea on mutant Huntingtin induced phenotypes. We tested the effects of green tea infusion on mutant Huntingtin induced neurodegeneration, impaired motor performance, reduced viability and lifespan by pseudopupil assay, climbing assay, eclosion and survival tests, respectively. We used immunoblots to measure Huntingtin protein levels and tested generic health benefits of green tea by longevity analysis.Results: We found that green tea supplementation reduced mutant Huntingtin induced neurodegeneration in Drosophila and positively impacted the longevity of mutant Huntingtin expressing flies. However, green tea did not rescue reduced viability of Drosophila expressing mutant Huntingtin or increased longevity of wild-type fruit flies.Discussion: Our results indicate that green tea consumption might have a modest positive effect on symptoms of HD.

Cortical Axonal Secretion of BDNF in the Striatum Is Disrupted in the Mutant-huntingtin Knock-in Mouse Model of Huntington's Disease

Deficient BDNF signaling is known to be involved in neurodegenerative diseases such as Huntington's disease (HD). Mutant huntingtin (mhtt)-mediated disruption of either BDNF transcription or transport is thought to be a factor contributing to striatal atrophy in the HD brain. Whether and how activity-dependent BDNF secretion is affected by the mhtt remains unclear. In the present study, I provide evidence for differential effects of the mhtt on cortical BDNF secretion in the striatum during HD progression. By two-photon imaging of fluorescent BDNF sensor (BDNF-pHluorin and -EGFP) in acute striatal slices of HD knock-in model mice, I found deficient cortical BDNF secretion regardless of the HD onset, but antisense oligonucleotide (ASO)-mediated reduction of htts only rescues BDNF secretion in the early HD brain before the disease onset. Although secretion modes of individual BDNF-containing vesicle were not altered in the pre-symptomatic brain, the full-fusion and partial-fusion modes of BDNF-containing vesicles were significantly altered after the onset of HD symptoms. Thus, besides abnormal BDNF transcription and transport, our results suggest that mhtt-mediated alteration in activity-dependent BDNF secretion at corticostriatal synapses also contributes to the development of HD.

Understanding patient-reported outcome measures in Huntington disease: at what point is cognitive impairment related to poor measurement reliability?

Symptom progression in Huntington disease (HD) is associated with cognitive decline which may interfere with the self-report of symptoms. Unfortunately, data to support or refute the psychometric reliability of patient-reported outcomes (PROs) as HD progresses are limited. This is problematic given that PROs are increasingly recognized as important measures of efficacy for new treatments. We examined PRO data from the HDQLIFE Measurement System (Speech Difficulties; Swallowing Difficulties; Chorea) in 509 individuals with premanifest, early-stage, or late-stage HD. Clinician-administered assessments of motor functioning (items from the UHDRS) and standardized objective assessments of cognition (Stroop, Symbol Digit Modalities) were also collected. We examined item bias using differential item functioning (DIF) across HD stage (premanifest, early-, late-) and relative to cognitive performance. We also examined the correlations between self-report and clinician ratings. Regression models that considered total cognitive ability were utilized to determine psychometric reliability of the PROs. Most PRO items were free from DIF for both staging and cognition. There were modest correlations between PROs and clinician report (ranged from - 0.40 to - 0.60). Modeling analyses indicated that psychometric reliability breaks down with poorer cognition and more progressed disease stage; split-half reliability was compromised (i.e., split-half reliability < 0.80) when scores were < 136 for Chorea, < 109 for Speech Difficulties, and < 179 for Swallowing Difficulties. Results indicate that the psychometric reliability of PROs can be compromised as HD symptoms progress and cognition declines. Clinicians should consider PROs in conjunction with other types of assessments when total cognition scores exceed critical thresholds.

RNAi-Based GluN3A Silencing Prevents and Reverses Disease Phenotypes Induced by Mutant huntingtin.

Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by expansion of a polyglutamine tract in the huntingtin protein. HD symptoms include severe motor, cognitive, and psychiatric impairments that result from dysfunction and later degeneration of medium-sized spiny neurons (MSNs) in the striatum. A key early pathogenic mechanism is dysregulated synaptic transmission due to enhanced surface expression of juvenile NMDA-type glutamate receptors containing GluN3A subunits, which trigger the aberrant pruning of synapses formed by cortical afferents onto MSNs. Here, we tested the therapeutic potential of silencing GluN3A expression in YAC128 mice, a well-established HD model. Recombinant adeno-associated viruses encoding a short-hairpin RNA against GluN3A (rAAV-shGluN3A) were generated, and the ability of different serotypes to transduce MSNs was compared. A single injection of rAAV9-shGluN3A into the striatum of 1-month-old mice drove potent (>90%) and long-lasting reductions of GluN3A expression in MSNs, prevented dendritic spine loss and improved motor performance in YAC128 mice. Later delivery, when spine pathology is already apparent, was also effective. Our data provide proof-of-concept for GluN3A silencing as a beneficial strategy to prevent or reverse corticostriatal disconnectivity and motor impairment in HD and support the use of RNAi-based or small-molecule approaches for harnessing this therapeutic potential.

Working Memory-Related Effective Connectivity in Huntington's Disease Patients.

Huntington’s disease (HD) is a genetically caused neurodegenerative disorder characterized by heterogeneous motor, psychiatric, and cognitive symptoms. Although motor symptoms may be the most prominent presentation, cognitive symptoms such as memory deficits and executive dysfunction typically co-occur. We used functional magnetic resonance imaging (fMRI) and task fMRI-based dynamic causal modeling (DCM) to evaluate HD-related changes in the neural network underlying working memory (WM). Sixty-four pre-symptomatic HD mutation carriers (preHD), 20 patients with early manifest HD symptoms (earlyHD), and 83 healthy control subjects performed an n-back fMRI task with two levels of WM load. Effective connectivity was assessed in five predefined regions of interest, comprising bilateral inferior parietal cortex, left anterior cingulate cortex, and bilateral dorsolateral prefrontal cortex. HD mutation carriers performed less accurately and more slowly at high WM load compared with the control group. While between-group comparisons of brain activation did not reveal differential recruitment of the cortical WM network in mutation carriers, comparisons of brain connectivity as identified with DCM revealed a number of group differences across the whole WM network. Most strikingly, we observed decreasing connectivity from several regions toward right dorsolateral prefrontal cortex (rDLPFC) in preHD and even more so in earlyHD. The deterioration in rDLPFC connectivity complements results from previous studies and might mirror beginning cortical neural decline at premanifest and early manifest stages of HD. We were able to characterize effective connectivity in a WM network of HD mutation carriers yielding further insight into patterns of cognitive decline and accompanying neural deterioration.

Inhibition of endocannabinoid degradation rectifies motivational and dopaminergic deficits in the Q175 mouse model of Huntington's disease.

Prominent motor deficits (e.g., chorea) that typify Huntington's disease (HD) arise following a prolonged prodromal stage characterized by psychiatric disturbances. Apathy, a disorder of motivation characterized by diminished goal-directed behavior, is one of the earliest and most common psychiatric symptoms in HD, but the underlying neurobiology is unclear and treatment options are limited. Alterations in the endocannabinoid (eCB) and dopamine systems represent prominent pathophysiological markers in HD that-similar to motivational deficits-present early and decline across disease progression. Whether changes in dopamine and eCB systems are associated with specific behavioral impairments in HD and whether these deficits are amenable to viable treatments is unknown. Here, we show that dopaminergic encoding of effortful drive progressively declines with age in an HD mouse model, and is restored by elevating tissue levels of the eCB 2-arachidonoylglycerol (2-AG) through targeted inhibition of its enzymatic degradation. This work supports aberrant dopaminergic encoding of reward as a neurobiological correlate of apathy in HD, and indicates that cannabinoid receptor-based therapies may benefit neuropsychiatric care for HD.

Mutant Huntingtin Causes a Selective Decrease in the Expression of Synaptic Vesicle Protein 2C

Huntington's disease (HD) is a neurodegenerative disease caused by a polyglutamine expansion in the huntingtin (Htt) protein. Mutant Htt causes synaptic transmission dysfunctions by interfering in the expression of synaptic proteins, leading to early HD symptoms. Synaptic vesicle proteins 2 (SV2s), a family of synaptic vesicle proteins including 3 members, SV2A, SV2B, and SV2C, plays important roles in synaptic physiology. Here, we investigated whether the expression of SV2s is affected by mutant Htt in the brains of HD transgenic (TG) mice and Neuro2a mouse neuroblastoma cells (N2a cells) expressing mutant Htt. Western blot analysis showed that the protein levels of SV2A and SV2B were not significantly changed in the brains of HD TG mice expressing mutant Htt with 82 glutamine repeats. However, in the TG mouse brain there was a dramatic decrease in the protein level of SV2C, which has a restricted distribution pattern in regions particularly vulnerable in HD. Immunostaining revealed that the immunoreactivity of SV2C was progressively weakened in the basal ganglia and hippocampus of TG mice. RT-PCR demonstrated that the mRNA level of SV2C progressively declined in the TG mouse brain without detectable changes in the mRNA levels of SV2A and SV2B, indicating that mutant Htt selectively inhibits the transcriptional expression of SV2C. Furthermore, we found that only SV2C expression was progressively inhibited in N2a cells expressing a mutant Htt containing 120 glutamine repeats. These findings suggest that the synaptic dysfunction in HD results from the mutant Htt-mediated inhibition of SV2C transcriptional expression. These data also imply that the restricted distribution and decreased expression of SV2C contribute to the brain region-selective pathology of HD.

Huntington’s disease: Managing neuropsychiatric symptoms in Huntington’s disease

This clinical update review focuses on the management of the neuropsychiatric manifestations of Huntington's disease (HD). The review highlights current issues regarding pharmacological and non-pharmacological treatment, putative therapeutics and recent relevant research findings in this area. Neuropsychiatric symptoms may precede the classic motor clinical symptoms of HD (prodromal HD) by decades and cause significant functional impairment. Early recognition and comprehensive non-pharmacological, usually in combination with pharmacological, treatment is essential.

Initial Deutetrabenazine Compliance, Satisfaction, and Patient Perception of Change in Huntington Disease Symptoms (P4.040)

Initial Deutetrabenazine Compliance, Satisfaction, and Patient Perception of Change in Huntington Disease Symptoms (P4.040)

A Study of Triplet-Primed PCR for Identification of CAG Repeat Expansion in the HTT Gene in a Cohort of 503 Indian Cases with Huntington's Disease Symptoms.

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder with an average age at onset of 40years. It is a polyglutamine (polyQ) disorder that is caused by an increase in the number of CAG repeats in the huntingtin (HTT) gene. Genetic tests that accurately determine the number of CAG repeats are performed for confirmation of diagnosis, predictive testing of persons at genetic risk for inheriting HD, and prenatal testing. The aim of our study was to evaluate efficacy of triplet-primed polymerase chain reaction (TP-PCR) for routine diagnosis of HD in suspected cases from India. We evaluated a combination of CAG flanking PCR and triplet-primed PCR for estimation of CAG repeats in 503 cases with clinical suspicion of HD. There were 250 cases (49.7%) that showed thepresence of expanded alleles, with 241 (47.9%) being fully penetrant alleles and nine (1.8%) in the reduced penetrance category. There were seven juvenile cases with an age of onset of < 20years, with the longest allele comprising 106 CAG repeats found in an 8-year-old male patient. The results demonstrated an inverse (R = - 0.67) relationship between CAG length and age at clinical onset. Our study on pan-Indian cases is one of the largest studies reported so far in India and focuses on the most accurate and comprehensive molecular diagnostic evaluation of HD.

A Genetic Study of Psychosis in Huntington's Disease: Evidence for the Involvement of Glutamate Signaling Pathways.

Psychotic symptoms of delusions and hallucinations occur in about 5% of persons with Huntington's disease (HD). The mechanisms underlying these occurrences are unknown, but the same symptoms also occur in schizophrenia, and thus genetic risk factors for schizophrenia may be relevant to the development of psychosis in HD. To investigate the possible role of genes associated with schizophrenia in the occurrence of psychotic symptoms in HD. DNA from subjects with HD and psychosis (HD+P; n = 47), subjects with HD and no psychosis (HD-P; n = 126), and controls (CTLs; n = 207) was genotyped using the Infinium PsychArray-24 v1.1 BeadChip. The allele frequencies of single-nucleotide polymorphisms (SNPs) that were previously associated with schizophrenia and related psychiatric disorders were compared between these groups. Of the 30 candidate genes tested, 10 showed an association with psychosis in HD. The majority of these genes, including CTNNA2, DRD2, ERBB4, GRID2, GRIK4, GRM1, NRG1, PCNT, RELN, and SLC1A2, demonstrate network interactions related to glutamate signaling. This study suggests genetic associations between several previously identified candidate genes for schizophrenia and the occurrence of psychotic symptoms in HD. These data support the potential role of genes related to glutamate signaling in HD psychosis.

Cerebrospinal fluid sCD27 levels indicate active T cell-mediated inflammation in premanifest Huntington's disease.

IntroductionHuntington’s disease (HD) is a neurodegenerative disorder, but evidence also suggests neuroinflammation in the pathogenesis. The immune mechanisms involved and the timing of their activation need further clarification.MethodsA clinically well-characterized HD cohort and gene negative controls were enrolled. YKL-40 reflecting innate immunity and sCD27, a marker of adaptive immunity, were measured across disease stages. Comparisons were made with markers of neurodegeneration: neurofilament light (NFL), total-tau (T-tau), and phospho-tau (P-tau).Results52 cross-sectional cerebrospinal fluid samples and 23 follow-up samples were analyzed. sCD27 was elevated in manifest HD and premanifest gene expansion carriers, whereas controls mostly had undetectable levels. YKL-40 showed a trend toward increase in manifest HD. sCD27 correlated with YKL-40 which in turn was closely associated to all included markers of neurodegeneration. YKL-40, NFL, and both forms of tau could all independently predict HD symptoms, but only NFL levels differed between groups after age-adjustment.ConclusionIncreased sCD27 in premanifest HD is a sign of T cell-mediated neuroinflammation. This finding is novel since other reports almost exclusively have found early involvement of innate immunity. Validation of sCD27 in a larger HD cohort is needed. The role of adaptive immunity in HD needs further clarification, as it may hasten disease progression.

Supplemental Treatment for Huntington’s Disease with miR-132 that Is Deficient in Huntington’s Disease Brain

Huntington’s disease (HD) is an intractable neurodegenerative disorder caused by mutant Huntingtin (HTT) proteins that adversely affect various biomolecules and genes. MicroRNAs (miRNAs), which are functional small non-coding RNAs, are also affected by mutant HTT proteins. Here, we show amelioration in motor function and lifespan of HD-model mice, R6/2 mice, by supplying miR-132 to HD brains using a recombinant adeno-associated virus (rAAV) miRNA expression system. miR-132 is an miRNA related to neuronal maturation and function, but the level of miR-132 in the brain of R6/2 mice was significantly lower than that of wild-type mice. Our miR-132 supplemental treatment, i.e., supplying miR-132 to the brain, produced symptomatic improvement or retarded disease progression in R6/2 mice; interestingly, it had little effect on disease-causing mutant HTT mRNA expression and its products. Therefore, the findings suggest that there may be a therapeutic way to treat HD without inhibiting and/or repairing disease-causing HTT genes and gene products. Although miR-132 supplement may not be a definitive treatment for HD, it may become a therapeutic method for relieving HD symptoms and delaying HD progression.

Systematic genetic interaction studies identify histone demethylase Utx as potential target for ameliorating Huntington's disease.

Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by alterations in the huntingtin gene (htt). Transcriptional dysregulation is an early event in HD progression. Protein acetylation and methylation particularly on histones regulates chromatin structure thereby preventing or facilitating transcription. Although protein acetylation has been found to affect HD symptoms, little is known about the potential role of protein methylation in HD pathology. In recent years, a series of proteins have been described that are responsible for methylating and demethylating histones as well as other proteins. We carried out systematic genetic interaction studies testing lysine and arginine methylases and demethylases in a Drosophila melanogaster HD model. We found that modulating methylation enzymes that typically affect histone positions H3K4, H3K36 or H3K79 had varying effects on HD pathology while modulating ones that typically affect constitutive heterochromatin marks at H3K9 and H4K20 generally had limited impact on HD pathology. In contrast, modulating enzymes acting on the facultative heterochromatin mark at H3K27 had specific effects on HD pathology, with reduction of the demethylase Utx rescuing HTT-induced pathology while reducing Polycomb Repressive Complex2 core methylase components led to more aggressive pathology. Further exploration of the mechanism underlying the methylation-specific interactions suggest that these lysine and arginine methylases and demethylases are likely exerting their influence through non-histone targets. These results highlight a novel therapeutic approach for HD in the form of Utx inhibition.

Apathy and atrophy of subcortical brain structures in Huntington's disease: A two-year follow-up study.

BackgroundHuntington's disease (HD) is characterized by motor and behavioral symptoms, and cognitive decline. HD gene carriers and their caregivers report the behavioral and cognitive symptoms as the most burdensome. Apathy is the most common behavioral symptom of HD and is related to clinical measures of disease progression, like functional capacity. However, it is unknown whether apathy is directly related to the neurodegenerative processes in HD.ObjectiveThe aim is to investigate whether an association between atrophy of subcortical structures and apathy is present in HD, at baseline and after 2 years follow-up.MethodVolumes of 7 subcortical structures were measured using structural T1 MRI in 171 HD gene carriers of the TRACK-HD study and apathy was assessed with the Problem Behaviors Assessment-Short, at baseline and follow-up visit. At baseline, logistic regression was used to evaluate whether volumes of subcortical brain structures were associated with the presence of apathy. Linear regression was used to assess whether subcortical atrophy was associated with the degree of apathy at baseline and with an increase in severity of apathy over time.ResultsAt baseline, smaller volume of the thalamus showed a higher probability of the presence of apathy in HD gene carriers, but none of the subcortical structures was associated with the degree of apathy. Over time, no association between atrophy of any subcortical structures and change in degree of apathy was found.ConclusionThe presence of apathy is associated with atrophy of the thalamus in HD, suggesting that apathy has an underlying neural cause and might explain the high incidence of apathy in HD. However, no association was found between atrophy of these subcortical structures and increase in severity of apathy over a 2-year time period.

Emotion Recognition Correlates With Social-Neuropsychiatric Dysfunction in Huntington's Disease.

People with Huntington's disease (HD) experience poor social quality of life, relationship breakdown, and social withdrawal, which are mediated to some extent by socially debilitating neuropsychiatric symptoms, such as apathy and disinhibition. Social cognitive symptoms, such as impaired emotion recognition, also occur in HD, however, the extent of their association with these socially debilitating neuropsychiatric symptoms is unknown. Our study examined the relationship between emotion recognition and symptom ratings of apathy and disinhibition in HD. Thirty-two people with premanifest or symptomatic-HD completed Part 1 of The Awareness of Social Inference Test (TASIT), which is a facial emotion recognition task. In addition, we obtained severity ratings for apathy and disinhibition on the Frontal Systems Behavior Scale (FrSBe) from a close family member. Our analyses used motor symptom severity as a proxy for disease progression. Emotion recognition performance was significantly associated with family-ratings of apathy, above and beyond their shared association with disease severity. We found a similar pattern for disinhibition ratings, which fell short of statistical significance. As expected, worse emotion recognition performance was correlated with higher severity in FrSBe symptom ratings. Our findings suggest that emotion recognition abilities relate to key socially debilitating neuropsychiatric symptoms in HD. Our results help to understand the functional significance of emotion recognition impairments in HD, and may have implications for the development of remediation programs aimed at improving patients' social quality of life. (JINS, 2018, 24, 417-423).

The Impact of Family History on the Clinical Features of Huntington’s Disease

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. In most cases the disease is inherited from a parent, although a considerable number of affected persons have no reported family history of the disease. While CAG repeat length is negatively correlated with age of symptom onset, variability exists suggesting that other variables may influence symptom onset. The objective of this study is to determine whether awareness of a family history of HD has an impact on symptom onset and disease manifestations. Data were obtained from Enroll-HD to compare subjects with a family history of HD to subjects without on various key clinical outcomes. In addition, multiple regressions were performed to investigate the impact of family history on the age at onset of depression and motor symptoms. 4,285 mutation positive subjects were included in the analysis, of which 4.81% had a negative family history. Controlling for CAG repeat length, a positive family history predicted an onset of depression 11.438 years earlier and an onset of motor symptoms 6.681 years earlier when compared to having a negative family history. Subjects with a positive family history were more likely to report behavioral manifestations as the initial major symptom of HD (38.6% vs. 29.6%, p = 0.023), and were more likely to report previous suicidal ideation/attempts (26.2% vs. 20.3%, p = 0.046). A positive family history of HD appears to be associated with an earlier onset of depression and overall disease manifestations. Implications regarding the role of genetic versus environmental contributions to symptom onset in HD are discussed.

How motor, behavioral and cognitive symptoms affect functional abilities in Huntington’s disease?

Background: Huntington’s disease (HD) is a rare autosomal dominant neurodegenerative condition that steeply affect patient’s motor, behavioral and cognitive domains making patients incapable of independent life. In this study we intend to explore how HD symptoms affect functional abilities.