Huntington's Disease Patients Research Articles

Sex contribution to average age at onset of Huntington’s disease depends on the number of (CAG)n repeats

Huntington’s disease (HD) is a hereditary neurodegenerative disorder caused by the extension of the CAG repeats in exon 1 of the HTT gene and is transmitted in a dominant manner. The present study aimed to assess whether patients’ sex, in the context of mutated and normal allele length, contributes to age on onset (AO) of HD. The study population comprised a large cohort of 3723 HD patients from the European Huntington’s Disease Network’s REGISTRY database collected at 160 sites across 17 European countries and in one location outside Europe. The data were analyzed using regression models and factorial analysis of variance (ANOVA) considering both mutated allele length and sex as predictors of patients’ AO. AO, as described by the rater’s estimate, was found to be later in affected women than in men across the whole population. This difference was most pronounced in a subgroup of 1273 patients with relatively short variants of the mutated allele (40–45 CAG repeats) and normal alleles in a higher half of length distribution—namely, more than 17 CAG repeats; however, it was also observed in each group. Our results presented in this observational study point to sex-related differences in AO, most pronounced in the presence of the short mutated and long normal allele, which may add to understanding the dynamics of AO in Huntington’s Disease.Trial registration: ClinicalTrials.gov identifier NCT01590589.

Stress in Huntington's Disease: Characteristics and Correlates in Patients and At-Risk Individuals.

Huntington's disease (HD) is a neurodegenerative disease that presents families with significant numbers of stressful events. However, relatively little empirical research has characterized the stressors encountered by members of HD-affected families and their correlations with psychological symptoms. This study examined frequencies of specific stressors in HD patients and at-risk individuals and the correlates of these stressors with demographics, disease characteristics, and symptoms of depression and anxiety. HD patients (n = 57) and at-risk individuals (n = 81) completed the Responses to Stress Questionnaire -Huntington's Disease Version to assess HD-related stressors. Participants completed measures of depression and anxiety symptoms. Patient health records were accessed to obtain information related to disease characteristics. Patients endorsed a mean number of 5.05 stressors (SD = 2.74) out of the 10-item list. Demographics were not related to total stressors, but disease characteristics were significantly related to specific stressors. At-risk individuals endorsed a mean number of 3.20 stressors (SD = 2.65) out of the 11-item list. Age and sex were significantly related to specific stressors. Total number of stressors was significantly related to depression (β=0.67, p < 0.001) and anxiety symptoms (β=0.58, p < 0.001) in patients and at-risk individuals (β=0.35, p = 0.003 and β=0.32, p = 0.006, respectively). hese findings emphasize the significant burden of stress experienced by HD patients and at-risk individuals. We highlight a need for more specific stress-based measures and psychosocial support interventions for HD-affected families.

Huntington Disease Treated with Austedo (Deutetrabenazine)

Huntington's disease (HD) is a neurodegenerative disorder characterized by chorea, cognitive decline, and psychiatric symptoms. Austedo (deutetrabenazine) represents a significant advancement in the treatment of chorea associated with HD, being the first deuterated drug approved by the US Food and Drug Administration (FDA) for this purpose. Deutetrabenazine, a modified form of tetrabenazine, acts by inhibiting vesicular monoamine transporter 2 (VMAT2), thereby reducing dopamine levels. Its unique structure, incorporating deuterium instead of hydrogen, prolongs its half-life and allows for less frequent dosing. Clinical trials, such as Phase III First HD, have demonstrated deutetrabenazine's efficacy in improving chorea symptoms in HD patients, with favorable tolerability reported. Despite similarities in effectiveness with tetrabenazine, deutetrabenazine offers a potentially better-tolerated option for chorea treatment in HD. However, further research, including direct comparative studies and long-term data, is necessary to fully elucidate its advantages over existing therapies.

Neuroprotective Effect of Boswellia serrata against 3-NP Induced Experimental Huntington’s Disease

Objectives:: The study aimed to assess the neuroprotective effect of Boswellia serrata against 3-NP-induced experimental Huntington’s disease. Background:: Previous studies have shown Boswellia to have sedative, analgesic, and anti-tumour effects. Boswellia serrata yields four pentacyclic triterpene acids and boswellic acid, a bioactive substance that prevents leukotriene biogenesis. Methods:: The potential neuroprotective effect of Boswellia serrata against 3-nitro propionic acid (3-NP)-induced Huntington's disease (HD) was examined at oral doses of 45 mg/kg, 90 mg/kg, and 180 mg/kg. In this study, HD was induced by 3-NP at a dose of 10 mg/kg in Wistar rats. The study used 56 Wistar rats (8 per group) for biochemical (inflammatory markers, acetylcholinesterase activity) and behavioural (elevated plus maze, Y-maze, open-field, tail suspension tests, etc.) assessments. Additionally, a histological examination of the brain was carried out. In addition, the analysis of Boswellia serrata extract was performed by different analytical techniques, like UV spectrophotometer, FTIR, and HPLC methods. Results:: In the brain, succinate dehydrogenase is a mitochondrial enzyme irreversibly inhibited by 3-NP. Administration of 3-NP resulted in HD with altered behavioural and motor changes in rats. Treatment with Boswellia serrata resulted in remarkable protection of rats against 3-NP-induced behaviour and motor deficits in a dose-dependent manner. Moreover, in rats administered with 3-NP, Boswellia serrata improved memory performance and lowered levels of inflammatory biomarkers. These results have also been supported by histopathological analysis. Acetyl-11-keto-p-boswellic acid was found to be the main active component of Boswellia serrata extract. Conclusion:: Boswellia serrata at a dose of 180 mg/kg exhibited better protection compared to the other doses against HD induced by 3-NP. More detailed studies based on molecular targets are needed for the Boswellia serrata to transition from the bench to the bedside for use as an adjuvant in HD patients.

Dermal Fibroblast Cell Line from a Patient with the Huntington's Disease as a Promising Model for Studying Disease Pathogenesis: Production and Characterization.

Huntington's disease (HD) is an incurable hereditary disease caused by expansion of the CAG repeats in the HTT gene encoding the mutant huntingtin protein (mHTT). Despite numerous studies in cellular and animal models, the mechanisms underlying the biological role of mHTT and its toxicity to striatal neurons have notyet been established and no effective therapy for HD patients has been developed so far. We produced and characterized a new line of dermal fibroblasts (HDDF, Huntington's disease dermal fibroblasts) from a patient with a confirmed HD diagnosis. We also studied the growth characteristics of HDDF cells, stained them for canonical markers, karyotyped these cells, and investigated their phenotype. HDDF cells was successfully reprogrammed into induced striatal neurons via transdifferentiation. The new fibroblast line can be used as a cell model to study the biological role of mHTT and manifestations of HD pathogenesis in both fibroblasts and induced neuronal cells obtained from them by reprogramming techniques.

Saccades, pupil response and blink abnormalities in Huntington’s disease patients during free viewing

ObjectiveVideo-based eye tracking was used to investigate saccade, pupil, and blink abnormalities among patients with Huntington’s disease (HD) who watched sequences of short videos. HD, an autosomal dominant neurodegenerative disorder resulting from a CAG mutation on chromosome 4, produces motor and cognitive impairments including slow or irregular eye movements, which have been studied using structured tasks. MethodsTo explore how HD affects eye movements under instruction free conditions, we assessed 22 HD patients and their age matched controls in a 10-minute video-based free viewing task. ResultsPatients with HD experienced a significant reduction in saccade exploration rate following video clip transitions, an increase in pupil reactions to luminance changes after clip transitions, and a significant higher blink rate throughout the task compared to the control group. ConclusionsThese results show that HD has a significant impact on how patients visually explore and respond to their environment under unconstrained and ecologically natural conditions. SignificanceEye tracking in HD patients revealed saccadic, pupil, and blink abnormalities in early HD patients, suggestive of brain circuitry abnormalities that probably involve brain stem deficits. Further research should explore the impact of these changes on the quality of life of the patients affected by the disease.

Uncovering the ferroptosis related mechanism of laduviglusib in the cell-type-specific targets of the striatum in Huntington’s disease

Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder featured by abnormal movements, arising from the extensive neuronal loss and glial dysfunction in the striatum. Although the causes and pathogenetic mechanisms of HD are well established, the development of disease-modifying pharmacological therapies for HD remains a formidable challenge. Laduviglusib has demonstrated neuroprotective effects through the enhancement of mitochondrial function in the striatum of HD animal models. Ferroptosis is a nonapoptotic form of cell death that occurs as a consequence of lethal iron-dependent lipid peroxidation and mitochondrial dysfunction. However, the ferroptosis-related mechanisms underlying the neuroprotective effects of laduviglusib in the striatum of HD patients remain largely uncharted. In this study, we leveraged single-nucleus RNA sequencing data obtained from the striatum of HD patients in stages 2–4 to identify differentially expressed genes within distinct cell-type. We subsequently integrated these differentially expressed genes of HD, laduviglusib target genes and ferroptosis-related genes to predict the ferroptosis-related mechanisms underpinning the neuroprotective effects of laduviglusib in HD patients. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses unveiled that the effects of laduviglusib on direct pathway striatal projection neurons (dSPNs) is mainly associated with Th17 cell differentiation pathways. Conversely, its impact on indirect pathway striatal projection neurons (iSPNs) extends to the Neurotrophin signaling pathway, FoxO signaling pathway, and reactive oxygen species pathway. In microglia, laduviglusib appears to contribute to HD pathology via mechanisms related to Th17 cell differentiation and the FoxO signaling pathway. Further, molecular docking results indicated favorable binding of laduviglusib with PARP1 (associated with dSPNs and iSPNs), SCD (associated with astrocytes), ALOX5 (associated with microglia), and HIF1A (associated with dSPNs, iSPNs, and microglia). In addition, the KEGG results suggest that laduviglusib may enhance mitochondrial function and protect against neuronal loss by targeting ferroptosis-related signaling pathways, particularly mediated by ALOX5 in microglia. These findings provide valuable insights into the potential mechanisms through which laduviglusib exerts its effects on distinct cell-types within the HD striatum.

Pathomechanisms of behavioral abnormalities in Huntington disease: an update.

Huntington disease (HD), a devastating autosomal-dominant neurodegenerative disease caused by an expanded CAG trinucleotide repeat, is clinically characterized by a triad of symptoms including involuntary motions, behavior problems and cognitive deficits. Behavioral symptoms with anxiety, irritability, obsessive-compulsive behaviors, apathy and other neuropsychiatric symptoms, occurring in over 50% of HD patients are important features of this disease and contribute to impairment of quality of life, but their pathophysiology is poorly understood. Behavior problems, more frequent than depression, can be manifest before obvious motor symptoms and occur across all HD stages, usually correlated with duration of illness. While specific neuropathological data are missing, the relations between gene expression and behavior have been elucidated in transgenic models of HD. Disruption of interneuronal communications, with involvement of prefronto-striato-thalamic networks and hippocampal dysfunctions produce deficits in multiple behavioral domains. These changes that have been confirmed by multistructural neuroimaging studies are due to a causal cascade linking molecular pathologies (glutamate-mediated excitotoxicity, mitochondrial dysfunctions inducing multiple biochemical and structural alterations) and deficits in multiple behavioral domains. The disruption of large-scale connectivities may explain the variability of behavior profiles and is useful in understanding the biological backgrounds of functional decline in HD. Such findings offer new avenues for targeted treatments in terms of minimizing neurobehavioral impairment in HD.

Risk Factors and Interventions for Suicide in Huntington's Disease-A Systematic Review.

Background/Objectives: Huntington's disease (HD) is an autosomal dominant genetic disorder causing progressive neurodegeneration which, aside from symptomatic therapies for controlling psychological and motor problems, currently has no effective treatment. People who receive this diagnosis often feel disoriented and lost without guidance. Furthermore, HD patients are estimated to have a two to seven times greater risk of suicide death compared to the general population. The current review investigates the complex relationship between HD and suicide, seeking to identify key risk factors influencing suicidal ideation and behaviour in affected individuals. Methods: We conducted a systematic review following the PRISMA guidelines. Studies were searched for on the PubMed, Cochrane, and Web of Science databases, and 17 articles met the inclusion criteria. Results: The findings reveal that emotional strain, neuropsychiatric symptoms, and the absence of a cure contribute to heightened suicidal tendencies in HD patients. Critical periods for suicide risk coincide with early symptomatic stages of disease or the successive phase, with the loss of independence impacting on daily functioning. Risk factors associated with HD include a depressive mood, cognitive impairments, and a history of suicide attempts. Conclusions: From a prevention perspective, a comprehensive multidisciplinary and multidimensional approach could enhance the overall well-being of people with HD. In particular, screening for suicidal thoughts in people with HD could mitigate suicide risk.

Sex differences in Huntington's disease from a neuroinflammation perspective.

Huntington's disease (HD) is a debilitating neurodegenerative condition characterized by motor, cognitive and psychiatric abnormalities. Immune dysregulation, prominently featuring increased immune activity, plays a significant role in HD pathogenesis. In addition to the central nervous system (CNS), systemic innate immune activation and inflammation are observed in HD patients, exacerbating the effects of the Huntingtin (HTT) gene mutation. Recent attention to sex differences in HD symptom severity underscores the need to consider gender as a biological variable in neurodegenerative disease research. Understanding sex-specific immune responses holds promise for elucidating HD pathophysiology and informing targeted treatment strategies to mitigate cognitive and functional decline. This perspective will highlight the importance of investigating gender influence in HD, particularly focusing on sex-specific immune responses predisposing individuals to disease.

A Comprehensive Perspective of Huntington’s Disease

Huntington's disease (HD) is a severe genetic illness caused by a CAG expansion on chromosome 4 in the huntingtin gene. This results in an excessively long polyglutamine tract, which has negative consequences. The normal huntingtin protein serves important tasks, however the mutant version causes a variety of detrimental effects. Disruptions in cellular processes such as autophagy, decreased mitochondrial activity, lysosomal dysfunction, and others are involved in the etiology of HD. Inflammation, oxidative stress, and transcriptional alterations all contribute to neurodegeneration. Despite great progress in understanding the genetic basis of HD, there is currently no cure. The current approach to management focuses on symptomatic control, but as our understanding of genetics advances, targeted medicines might become available. Although HD is still a difficult condition to treat, there is optimism for future advancements in research. Clinical techniques mostly focus on symptom management, with genetic testing assisting in diagnosis. Promising research looks on potential disease-modifying therapies, such as ways to reduce mutant huntingtin levels and improve clearance. Ongoing clinical research provide promise for future treatments, bringing hope to HD patients and their families.

Preserved VPS13A distribution and expression in Huntington's disease: divergent mechanisms of action for similar movement disorders?

VPS13A disease and Huntington's disease (HD) are two basal ganglia disorders that may be difficult to distinguish clinically because they have similar symptoms, neuropathological features, and cellular dysfunctions with selective degeneration of the medium spiny neurons of the striatum. However, their etiology is different. VPS13A disease is caused by a mutation in the VPS13A gene leading to a lack of protein in the cells, while HD is due to an expansion of CAG repeat in the huntingtin (Htt) gene, leading to aberrant accumulation of mutant Htt. Considering the similarities of both diseases regarding the selective degeneration of striatal medium spiny neurons, the involvement of VPS13A in the molecular mechanisms of HD pathophysiology cannot be discarded. We analyzed the VPS13A distribution in the striatum, cortex, hippocampus, and cerebellum of a transgenic mouse model of HD. We also quantified the VPS13A levels in the human cortex and putamen nucleus; and compared data on mutant Htt-induced changes in VPS13A expression from differential expression datasets. We found that VPS13A brain distribution or expression was unaltered in most situations with a decrease in the putamen of HD patients and small mRNA changes in the striatum and cerebellum of HD mice. We concluded that the selective susceptibility of the striatum in VPS13A disease and HD may be a consequence of disturbances in different cellular processes with convergent molecular mechanisms already to be elucidated.

Evidence of mutant huntingtin and tau-related pathology within neuronal grafts in Huntington’s disease cases

A number of post-mortem studies conducted in transplanted Huntington’s disease (HD) patients from various trials have reported the presence of pathological and misfolded proteins, in particular mutant huntingtin (mHtt) and phosphorylated tau neuropil threads, in the healthy grafted tissue. Here, we extended these observations with histological analysis of post-mortem tissue from three additional HD patients who had received similar striatal allografts from the fetal tissue transplantation trial conducted in Los Angeles in 1998. Immunohistochemical staining was performed using anti-mHtt antibodies, EM48 and MW7, as well as anti-hyperphosphorylated tau antibodies, AT8 and CP13. Immunofluorescence was used to assess the colocalization of EM48+ mHtt aggregates with the neuronal marker MAP2 and/or the extracellular matrix protein phosphacan in both the host and grafts. We confirmed the presence of mHtt aggregates within grafts of all three cases as well as tau neuropil threads in the grafts of two of the three transplanted HD patients. Phosphorylated tau was also variably expressed in the host cerebral cortex of all three subjects. While mHtt inclusions were present within neurons (immunofluorescence co-localization of MAP2 and EM48) as well as within the extracellular matrix of the host (immunofluorescence co-localization of phosphacan and EM48), their localization was limited to the extracellular matrix in the grafted tissue. This study corroborates previous findings that both mHtt and tau pathology can be found in the host and grafts of HD patients years post-grafting.

Mechanisms of synapse-to-nucleus calcium signalling in striatal neurons and impairments in Huntington's disease.

Huntington's disease (HD) is a monogenic disorder with autosomal dominant inheritance. In HD patients, neurons in the striatum and cortex degenerate, leading to motor, psychiatric and cognitive disorders. Dysregulated synaptic function and calcium handling are common in many neurodegenerative diseases, including HD. N-methyl-D-aspartate (NMDA) receptor function is enhanced in HD at extrasynaptic sites, altering the balance of calcium-dependent neuronal survival versus death signalling pathways. Endoplasmic reticulum (ER) calcium handling is also abnormal in HD. The ER, which is continuous with the nuclear envelope, is purportedly involved in nuclear calcium signalling; based on this, we hypothesised that nuclear calcium signalling is altered in HD. We explored this hypothesis with calcium imaging techniques, including simultaneous epifluorescent imaging of cytosolic and nuclear calcium using jRCaMP1b and GCaMP3 sensors, respectively, in striatal spiny projection neurons in cortical-striatal co-cultures from the YAC128 mouse model of HD. Our data show contributions from a variety of calcium channels to nuclear calcium signalling. NMDA receptors (NMDARs) play an essential role in initiating action potential-dependent calcium signalling to the nucleus, and ryanodine receptors (RyR) contribute to both cytosolic and nuclear calcium signals. Unlike previous reports in glutamatergic hippocampal and cortical neurons, we found that in GABAergic striatal neurons, L-type voltage-gated calcium channels (CaV) contribute to cytosolic, but not nuclear calcium signalling. Calcium imaging also suggests impairments in nuclear calcium signalling in HD striatal neurons, where spontaneous action potential-dependent calcium transients in the nucleus were smaller in YAC128 striatal neurons compared to those of wild-type (WT). Our results elucidate mechanisms involved in action potential-dependent nuclear calcium signalling in GABAergic striatal neurons, and have revealed a clear deficit in this signalling in HD.

Gut Microbiota as a Modifier of Huntington's Disease Pathogenesis.

Huntingtin (HTT) protein is expressed in most cell lineages, and the toxicity of mutant HTT in multiple organs may contribute to the neurological and psychiatric symptoms observed in Huntington's disease (HD). The proteostasis and neurotoxicity of mutant HTT are influenced by the intracellular milieu and responses to environmental signals. Recent research has highlighted a prominent role of gut microbiota in brain and immune system development, aging, and the progression of neurological disorders. Several studies suggest that mutant HTT might disrupt the homeostasis of gut microbiota (known as dysbiosis) and impact the pathogenesis of HD. Dysbiosis has been observed in HD patients, and in animal models of the disease it coincides with mutant HTT aggregation, abnormal behaviors, and reduced lifespan. This review article aims to highlight the potential toxicity of mutant HTT in organs and pathways within the microbiota-gut-immune-central nervous system (CNS) axis. Understanding the functions of Wild-Type (WT) HTT and the toxicity of mutant HTT in these organs and the associated networks may elucidate novel pathogenic pathways, identify biomarkers and peripheral therapeutic targets for HD.

Molecular genetic analysis of cytosine-adenine-guanine repeats in huntingtin gene

Background: Huntington’s disease (HD) is a dominantly transmitted progressive neurodegenerative disorder due to abnormal expansion of cytosine-adenine-guanine (CAG) repeats in the huntingtin gene. Materials and Methods: The study involved a total of 35 HD patients identified through clinical evaluations. CAG repeats expansion analysis was conducted using polymerase chain reaction (PCR) to confirm positive cases. Results: Employing CAG flacking PCR in 35 cases, 19 tested positive, predominantly displaying CAG repeats in the range of 40–50. Noteworthy cases include a 5-month-old patient with 44 CAG repeats and an 80-year-old patient with 46 CAG repeats. Conclusion: The identification of the genetic defect in HD permits direct genetic testing to comprehend the complexities of HD in India, aiming for effective approaches in diagnosis, treatment, and prevention.

What Huntington's Disease Patients Say About Their Illness: An Online Direct-to-Participant Pilot Study.

Direct-to-participant online reporting facilitates the conduct of clinical research by increasing access and clinically meaningful patient engagement. We assessed feasibility of online data collection from adults with diagnosed Huntington's disease (HD) who directly reported their problems and impact in their own words. Data were collected online from consenting United States residents who self-identified as 1) having been diagnosed with Huntington's disease, 2) able to ambulate independently, and 3) self-sufficient for most daily needs. Data for this pilot study were collected using the Huntington Study Group myHDstory online research platform. The Huntington Disease Patient Report of Problems (HD-PROP), an open-ended questionnaire, was used to capture verbatim bothersome problems and functional impact. Natural language processing, human-in-the-loop curation of verbatim reports involving clinical and experience experts, and machine learning classified verbatim-reports into clinically meaningful symptoms. All 8 questionnaires in the online pilot study were completed by 345 participants who were 60.9% men, 34.5±9.9 (mean±SD) years old, and 9.5±8.4 years since HD diagnosis. Racial self-identification was 46.4% Caucasian, 28.7% African American, 15.4% American Indian/Alaska Native, and 9.5% other. Accuracy of verbatim classification was 99%. Non-motor problems were the most frequently reported symptoms; depression and cognitive impairment were the most common. Online research participation was feasible for a diverse cohort of adults who self-reported an HD diagnosis and predominantly non-motor symptoms related to mood and cognition. Online research tools can help inform what bothers HD patients, identify clinically meaningful outcomes, and facilitate participation by diverse and under-represented populations.

A Fast-Binding, Functionally Reversible, COX-2 Radiotracer for CNS PET Imaging.

Cyclooxygenase-2 (COX-2) is an enzyme that plays a pivotal role in peripheral inflammation and pain via the prostaglandin pathway. In the central nervous system (CNS), COX-2 is implicated in neurodegenerative and psychiatric disorders as a potential therapeutic target and biomarker. However, clinical studies with COX-2 have yielded inconsistent results, partly due to limited mechanistic understanding of how COX-2 activity relates to CNS pathology. Therefore, developing COX-2 positron emission tomography (PET) radiotracers for human neuroimaging is of interest. This study introduces [11C]BRD1158, which is a potent and uniquely fast-binding, selective COX-2 PET radiotracer. [11C]BRD1158 was developed by prioritizing potency at COX-2, isoform selectivity over COX-1, fast binding kinetics, and free fraction in the brain. Evaluated through in vivo PET neuroimaging in rodent models with human COX-2 overexpression, [11C]BRD1158 demonstrated high brain uptake, fast target-engagement, functional reversibility, and excellent specific binding, which is advantageous for human imaging applications. Lastly, post-mortem samples from Huntington's disease (HD) patients and preclinical HD mouse models showed that COX-2 levels were elevated specifically in disease-affected brain regions, primarily from increased expression in microglia. These findings indicate that COX-2 holds promise as a novel clinical marker of HD onset and progression, one of many potential applications of [11C]BRD1158 human PET.

Influence of anosognosia on patient-reported outcomes for psychiatric symptoms and quality of life in Huntington's disease

IntroductionAnosognosia, defined as reduced awareness of one's deficit or symptom, is common in Huntington's disease (HD) and detectable at each disease stage. The impact of anosognosia on self-reporting in HD populations is critical to understand given growing use of patient-reported outcomes in HD clinical care and research. We aimed to determine the influence of anosognosia on patient-reported outcome measures assessing psychiatric symptoms and quality of life in HD. MethodsWe enrolled HD patients to complete a battery of patient-reported and rater-administered measures, including the Anosognosia Scale, at baseline and 6 months later. Patient-reported outcome measures included NeuroQoL short forms for depression, anxiety, satisfaction with social roles and activities, and positive affect and well-being and Patient-Reported Outcomes Measurement Information System short forms for emotional distress-anger and sleep-related impairment. Anosognosia Scale-Difference Score indexed patient-clinician agreement on patient motor, cognitive, and behavioral abilities. We conducted multivariable linear regression analyses to quantify the association of baseline anosognosia with 6-month patient-reported outcomes. ResultsOf 79 patients with complete Anosognosia Scale data at baseline, 25 (31.6 %) met the scale's criterion for anosognosia. In the regression analyses, baseline Difference Score improved prediction of 6-month patient-reported outcomes for depression, anxiety, anger, and positive affect and well-being (χ2(1) value range for likelihood ratio tests contrasting models with and without Difference Score: 13.1–20.9, p-values <0.001). Patients with more anosognosia self-reported less severe psychiatric symptoms and more positive affect and well-being. ConclusionStudy results suggest that anosognosia influences patient-reported outcomes for psychiatric symptoms and quality of life in HD populations.

The utility of the irritability scale in Huntington's disease patients with evidence of irritability or aggression

IntroductionIrritability, a common neuropsychiatric symptom in Huntington's disease (HD), lacks a standardized measurement. The Irritability Scale (IS), tailored for HD, has patient and informant versions, but variable interrater agreement has been reported frequently in previous studies. To enhance the clinical utility of the IS, this study aimed to identify the most reliable components estimating the underlying construct and develop a shortened version for time-limited contexts. MethodsParticipant and informant/observer concordance and the relationship of individual items to the complete IS scale were assessed. The short-form (SF) items were selected based on interrater agreement, exploratory factor analysis (EFA), and Item Response Theory (IRT) analysis results. Pair-wise correlation and covariance models were used to examine how SF predicted total IS score in 106 participants from the STAIR (Safety, Tolerability, and Activity of SRX246 in Irritable Subjects with Huntington's Disease) trial. Item Response Theory (IRT) analysis was used to evaluate the range and function of the selected items. ResultsIS interrater agreement was statistically significant (r = 0.33, p = .001). In combination with EFA factors and IRT analyses, five items were identified that showed good reliability and performance in differentiating levels of irritability. ConclusionThe proposed 5-item SF IS provided a reliable measure of the full scale and may be less burdensome for use in a clinical setting.