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

Background: 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. Objective: 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. Methods: 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. Results: 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 (ß=0.67, p < 0.001) and anxiety symptoms (ß=0.58, p < 0.001) in patients and at-risk individuals (ß=0.35, p = 0.003 and ß=0.32, p = 0.006, respectively). Conclusions: 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.

Intrapersonal and Interpersonal Disengagement Coping: Associations with Emotions of Youth At-Risk for Huntington's Disease.

BACKGROUND: Families in which a parent has Huntington's disease (HD) are faced with significant stressors that can contribute to difficulties in communicating together about illness-related concerns. Family members who use more disengagement coping strategies, including denial and avoidance, to deal with illness-related stressors may have the greatest challenges to effective communication. OBJECTIVE: The current study examined the associations of intrapersonal and interpersonal disengagement coping responses with observed and reported emotions of adolescents and young adults (AYA) at genetic risk for HD. METHODS: Families included 42 AYA (n = 26 females) ages 10 to 34 (M = 19 years, 11 months; SD = 7 years, 6 months) and their parent with HD (n = 22 females, M age = 46 years, 10 months; SD = 9 years, 2 months). Dyads participated in observations of communication and completed questionnaires about disengagement coping and internalizing symptoms. RESULTS: Disengagement coping of AYA was unrelated to their observed and reported emotional difficulties (intrapersonal coping). However, there was evidence for the importance of interpersonal disengagement coping, as AYA's negative affect was observed and reported to be highest when both AYA and their parents reported using high levels of avoidance, denial, and wishful thinking to cope with HD-related stress. CONCLUSION: The findings underscore the importance of a family-oriented approach to coping and communication in families affected by HD.

Impairments to executive function in emerging adults with Huntington disease.

BACKGROUND AND OBJECTIVES: The clinical diagnosis of Huntington disease (HD) is typically made once motor symptoms and chorea are evident. Recent reports highlight the onset of cognitive and psychiatric symptoms before motor manifestations. These findings support further investigations of cognitive function across the lifespan of HD sufferers. METHODS: To assess cognitive symptoms in the developing brain, we administered assessments from the National Institutes of Health Toolbox Cognitive Battery, an age-appropriate cognitive assessment with population norms, to a cohort of children, adolescents and young adults with (gene-expanded; GE) and without (gene-not-expanded; GNE) the trinucleotide cytosine, adenine, guanine (CAG) expansion in the Huntingtin gene. These five assessments that focus on executive function are well validated and form a composite score, with population norms. We modelled these scores across age, and CAP score to estimate the slope of progression, comparing these results to motor symptoms. RESULTS: We find significant deficits in the composite measure of executive function in GE compared with GNE participants. GE participant performance on working memory was significantly lower compared with GNE participants. Modelling these results over age suggests that these deficits occur as early as 18 years of age, long before motor manifestations of HD. CONCLUSIONS: This work provides strong evidence that impairments in executive function occur as early as the second decade of life, well before anticipated motor onset. Future investigations should delineate whether these impairments in executive function are due to abnormalities in neurodevelopment or early sequelae of a neurodegenerative process.

Inhibitory control, working memory and coping with stress: Associations with symptoms of anxiety and depression in adults with Huntington's disease.

OBJECTIVE: Huntington's disease (HD) is an autosomal dominant neurodegenerative disease characterized by neuropsychiatric symptoms (e.g., anxiety and depression), where individuals suffer high levels of stress from the social, physical, and cognitive burden of the disease. The present study examined two factors associated with increased risk for symptoms of anxiety and depression: executive function skills (inhibitory control/attention and working memory) and skills to cope with stress. METHOD: Adults with HD completed the NIH Toolbox measures of inhibitory control/attention and working memory, as well as self-report measures of coping with HD-related stress and symptoms of anxiety and depression. Path analyses were used to test direct and indirect associations among the subtypes of executive functioning, coping, and symptoms. RESULTS: No significant associations were found in the full sample (n = 47), due to a significant portion of the sample with very low executive function abilities. Additional analyses were conducted on a subset of the sample (participants in the top three quartiles on both measures of executive functioning, n = 32). Significant indirect associations emerged among inhibitory control/attention skills, secondary control coping (e.g., acceptance and reappraisal), and symptoms of anxiety and depression in the subsample. Higher inhibitory control/attention skills were associated with greater use of secondary control coping, and greater use of these coping skills was related to lower symptoms of anxiety and depression. No direct or indirect associations were found among working memory skills, coping, and symptoms of anxiety and depression. CONCLUSIONS: Implications for interventions to enhance executive function and coping skills in adults with HD are highlighted. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Improving Patient Outreach by Defining Telehealth Suitability in a Tertiary Huntington's Disease Clinic.

BACKGROUND: The COVID-19 pandemic has increased the need for remote healthcare options among patients with Huntington's disease (HD). However, since not every HD patient is suitable for telehealth, it is important to differentiate who can be seen virtually from who should remain as in-person. Unfortunately, there are no clinical guidelines on how to evaluate HD patients for telehealth eligibility. OBJECTIVE: To standardize the teleneurology selection process in HD by implementing a screening tool that accounts for patient-specific factors. METHODS: We organized various indications and contraindications to teleneurology into a flowchart. If any indications or contraindications were met, patients were assigned to telehealth or maintained as in-person, respectively. If no indications or contraindications were met, patients were given the option of telehealth or in-person for their upcoming appointments. In two implementation cycles, we tested this screening tool among all HD patients scheduled for clinic visits, aided by chart review and phone interview. RESULTS: In a cohort of 81 patients, telehealth acceptance among eligible patients increased from 45.0%to 83.3%. Frequency of telehealth visits increased from a pre-intervention baseline of 12.8%to 28.2%. CONCLUSION: Teleneurology utilization among HD patients more than doubled across our study. Our intervention promotes consistency and patient-centeredness in HD clinical care and streamlines the overall telehealth selection process. Future studies can seek to reduce telehealth no-shows and also evaluate the utility of the motor and psychiatric criteria included in our screening tool.

Medicolegal Aspects of Huntington Disease.

Unlawful behaviors have been reported in association with Huntington's disease (HD), although their overall prevalence and clinical significance remain unknown. Recognition of problematic behavior is limited by stigma and lack of routine clinical assessment, as well as the absence of validated screening measures. We performed a retrospective chart review of 289 patients treated for HD at Vanderbilt University Medical Center from 2006 to 2020 to assess the frequency of illegal activity in our HD population. We identified 31 patients with HD who have a documented history of unlawful behavior, comprising 11 percent of the charts reviewed. Physical violence was the most common behavior reported, followed by reckless driving, substance abuse, illegal financial activity, and inappropriate sexual behavior. Mean age at the time of the first offense was 37 years. Patients with criminal offenses were more likely to be male and in the early stages of disease with associated psychiatric symptoms. Our results emphasize that illegal activities are a significant clinical problem in individuals with HD, particularly young adult males with comorbid psychiatric symptoms. These findings highlight the need for improved screening measures to detect high-risk behaviors in individuals with HD, as well as evidence-based protocols to guide triage and management of patients engaging in potentially detrimental activities.

Neurobiological and Psychosocial Correlates of Communication Between Huntington's Disease Patients and Their Offspring.

OBJECTIVE: Huntington's disease (HD) is an autosomal dominant neurodegenerative disease that presents significant challenges to family communication. The investigators examined observations of communication between parents with HD and their offspring talking about the challenges of HD and explored potential correlates of their communication. METHODS: The sample included parents with HD and their adolescent and young-adult offspring (N=64). Parent communication and chorea were independently coded from video recordings. Parents and offspring completed working memory assessments and self-reports of neuropsychiatric symptoms, stress, and coping. RESULTS: Evidence was found for the association of observed parent-offspring communication with disease markers, psychosocial characteristics, and neurocognitive function. For parents, disease markers and working memory were correlates of communication, whereas offspring's psychiatric symptoms, stress, and coping were associated with their communication. CONCLUSIONS: These findings have potential implications for clinical interventions to enhance communication and quality of life for HD families.

Healthcare Delivery and Huntington's Disease During the Time of COVID-19.

BACKGROUND: Safer-at-home orders during the COVID-19 pandemic altered the structure of clinical care for Huntington's disease (HD) patients. This shift provided an opportunity to identify limitations in the current healthcare infrastructure and how these may impact the health and well-being of persons with HD. OBJECTIVE: The study objectives were to assess the feasibility of remote healthcare delivery in HD patients, to identify socioeconomic factors which may explain differences in feasibility and to evaluate the impact of safer-at-home orders on HD patient stress levels. METHODS: This observational study of a clinical HD population during the 'safer-at-home' orders asked patients or caregivers about their current access to healthcare resources and patient stress levels. A chart review allowed for an assessment of socioeconomic status and characterization of HD severity. RESULTS: Two-hundred and twelve HD patients were contacted with 156 completing the survey. During safer-at-home orders, the majority of HD patients were able to obtain medications and see a physician; however, 25% of patients would not commit to regular telehealth visits, and less than 50% utilized an online healthcare platform. We found that 37% of participants were divorced/single, 39% had less than a high school diploma, and nearly 20% were uninsured or on low-income health insurance. Patient stress levels correlated with disease burden. CONCLUSION: A significant portion of HD participants were not willing to participate in telehealth services. Potential explanations for these limitations may include socioeconomic barriers and caregiving structure. These observations illustrate areas for clinical care improvement to address healthcare disparities in the HD community.

Risk-Taking Behaviors in Huntington's Disease.

BACKGROUND: Risky behaviors are common in Huntington's disease (HD) and can lead to significant adverse consequences. However, the prevalence and scope of these symptoms have not been studied systematically, and no empirically validated measures are available to screen for them. OBJECTIVE: To test a novel screening tool designed to assess risk-taking behaviors in HD. METHODS: We administered the Risk Behavior Questionnaire (RBQ-HD) to HD patients and caregivers at Vanderbilt University Medical Center between 2018-2019. Patients completed the questionnaire based on self-report; caregivers provided collateral reports. Clinical and demographic information were obtained from the electronic medical record. RESULTS: 60 patients and 60 caregivers completed the RBQ-HD. 80% of patients (n = 48) and 91.7% of caregivers (n = 60) reported at least one risky behavior. Adverse social behaviors, impulsive/compulsive behaviors, and reckless driving were the most common behavioral domains reported. Male patients were more likely to report risky behaviors than females (92.3% vs. 70.6%, p = 0.04). The number of risky behaviors reported by patients and caregivers was negatively correlated with patient age (r = -0.32, p = 0.01; r = -0.47, p = 0.0001, respectively). Patient and caregiver reports were highly correlated in matched pairs (n = 30; r = 0.63, p = 0.0002). CONCLUSION: These findings emphasize that risky behaviors are highly prevalent in HD and can be effectively identified through the use of a novel screening measure. We hypothesize that early pathological involvement of frontostriatal and mesolimbic networks may be important factors in the development of these behaviors.

Investigating the interplay of working memory, affective symptoms, and coping with stress in offspring of parents with Huntington's disease.

OBJECTIVE: The offspring of parents with Huntington's disease (HD) are faced with substantial levels of chronic uncontrollable and unpredictable stress. These stressors may place them at heightened risk of psychological distress and negative effects on executive functioning. This study investigated working memory, secondary control coping strategies (e.g., cognitive reappraisal, acceptance, distraction), and symptoms of anxiety/depression in offspring at risk for HD. METHOD: Adolescent (ages 10-19) and young adult (ages 20-29) offspring (n = 33; mean [M] age = 19.12 years, standard deviation [SD] = 6.01 years; 61% female) of parents with HD were recruited in a Huntington Disease Society of America Level 1 Center of Excellence. Participants completed self-report measures of coping and neuropsychiatric symptoms (i.e., anxiety, depression) and a standardized working memory assessment. Pearson correlations and path analyses were used to test associations. RESULTS: Participant scores on the working memory assessment were significantly lower compared with normative data, and scores on a mixed anxiety/depression scale revealed a significant elevation compared with normative data. Working memory, secondary control coping, and symptoms of anxiety/depression were significantly correlated. Analyses of the full model revealed that the total indirect effect of working memory on anxiety/depression through secondary control coping was significant (ß = -0.20). CONCLUSION: Secondary control coping skills are an important factor in understanding the relationship between working memory and symptoms of anxiety/depression in the offspring of parents with HD. Future longitudinal research is needed to establish the direction of these associations. Working memory and coping skills represent potential targets for intervention to reduce the risk of anxiety/depression in this population. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Allosteric activation of MALT1 by its ubiquitin-binding Ig3 domain.

The catalytic activity of the protease MALT1 is required for adaptive immune responses and regulatory T (Treg)-cell development, while dysregulated MALT1 activity can lead to lymphoma. MALT1 activation requires its monoubiquitination on lysine 644 (K644) within the Ig3 domain, localized adjacent to the protease domain. The molecular requirements for MALT1 monoubiquitination and the mechanism by which monoubiquitination activates MALT1 had remained elusive. Here, we show that the Ig3 domain interacts directly with ubiquitin and that an intact Ig3-ubiquitin interaction surface is required for the conjugation of ubiquitin to K644. Moreover, by generating constitutively active MALT1 mutants that overcome the need for monoubiquitination, we reveal an allosteric communication between the ubiquitination site K644, the Ig3-protease interaction surface, and the active site of the protease domain. Finally, we show that MALT1 mutants that alter the Ig3-ubiquitin interface impact the biological response of T cells. Thus, ubiquitin binding by the Ig3 domain promotes MALT1 activation by an allosteric mechanism that is essential for its biological function.

Mediators of Change in Capnometry Guided Respiratory Intervention for Panic Disorder.

Capnometry guided respiratory interventions have shown promising results in the treatment of panic disorder, but mechanisms of change are not yet well-understood. The current study examined changes in end-tidal carbon dioxide (ETCO2), anxiety sensitivity, and perceived control as mediators of panic symptom change. Sixty-nine adults with panic disorder received 4 weeks of respiratory training, and panic symptom severity and potential mediators were assessed at Pre-treatment, Mid-treatment, Post-treatment, 2-month follow-up, and 12-month follow-up. Multilevel mediation analyses showed that changes in perceived control significantly mediated changes in panic disorder severity and that for individuals who were hypocapnic at pre-treatment, ETCO2 was a significant mediator of symptom outcome. Findings provide further evidence that changes in perceived control, and improvements in respiratory dysregulation for hypocapnic individuals specifically, underlie symptom improvement from capnometry guided respiratory intervention for panic disorder.

Predictive Relationship Between Parental Beliefs and Accommodation of Pediatric Anxiety.

Behavior performed by parents to assist a youth in avoiding or alleviating anxiety, known as accommodation, is ubiquitous among pediatric anxiety disorders and strongly related to poor treatment outcome. According to cognitive-behavioral theory, the beliefs parents hold regarding accommodation should predict parental accommodating behavior. Unfortunately, little is known about the beliefs parents hold regarding accommodation, as there exists no validated measure of this construct. First, the psychometric properties were examined for the Parental Accommodation Scale (PAS), a novel measure of parental accommodating behavior frequency (PAS-Behavior scale) and parental beliefs about accommodation (PAS-Belief scale). Second, the relationship between parental beliefs about accommodation and accommodation frequency was examined. Results provide preliminary evidence of the internal consistency and convergent validity of the PAS. Stronger positive beliefs about accommodation significantly predicted accommodation frequency, even after controlling for youth anxiety severity. Specifically, beliefs that accommodation prevents youth from losing behavioral and emotional control significantly predicted accommodation frequency. Therefore, efforts to decrease accommodation in clinical settings should involve correcting maladaptive parental beliefs about accommodation, with a particular emphasis on beliefs regarding the necessity of accommodation in preventing a youth from losing behavioral and emotional control.

A Multisite Benchmarking Trial of Capnometry Guided Respiratory Intervention for Panic Disorder in Naturalistic Treatment Settings.

Panic disorder (PD) is associated with hyperventilation. The efficacy of a brief respiratory feedback program for PD has been established. The aim of the present study was to expand these results by testing a similar program with more clinically representative patients and settings. Sixty-nine adults with PD received 4 weeks of Capnometry Guided Respiratory Intervention (CGRI) using Freespira, which provides feedback of end-tidal CO2 (PETCO2) and respiration rate (RR), in four non-academic clinical settings. This intervention is delivered via home use following initial training by a clinician and provides remote monitoring of client adherence and progress by the clinician. Outcomes were assessed post-treatment and at 2- and 12-month follow-up. CGRI was associated with an intent-to-treat response rate of 83% and a remission rate of 54%, and large decreases in panic severity. Similar decreases were found in functional impairment and in global illness severity. Gains were largely sustained at follow-up. PETCO2 moved from the slightly hypocapnic range to the normocapnic range. Benchmarking analyses against a previously-published controlled trial showed very similar outcomes, despite substantial differences in sample composition and treatment settings. The present study confirms prior clinical results and lends further support to the viability of CGRI in the treatment of PD.

Altered source memory retrieval is associated with pathological doubt in obsessive-compulsive disorder.

Individuals with obsessive-compulsive disorder (OCD) often complain of doubt related to memory. As neuropsychological research has demonstrated that individuals with OCD tend to focus on details and miss the larger context, the construct of source (contextual) memory may be particularly relevant to memory complaints in OCD. Memory for object versus contextual information relies on partially distinct regions within the prefrontal cortex, parietal and medial temporal lobe, and may be differentially impacted by OCD. In the present study, we sought to test the hypothesis that individuals with OCD exhibit impaired source memory retrieval using a novel memory paradigm - The Memory for Rooms Test (MFRT) - a four-room memory task in which participants walk through four rooms and attempt to encode and remember objects. Demographically matched individuals with OCD and healthy controls studied objects in the context of four rooms, and then completed a memory retrieval test while undergoing functional magnetic resonance imaging (fMRI). While no differences were observed in source memory accuracy, individuals with OCD exhibited greater task related activation in the posterior cingulate cortex (PCC) relative to healthy controls during correct source memory retrieval. During correct object recognition, individuals with OCD failed to recruit the dorsolateral prefrontal(DLPFC)/premotor, left mPFC, and right parietal regions to the same extent as healthy controls. Our results suggest abnormal recruitment of frontal-parietal and PCC regions during source verses object memory retrieval in OCD. Within the OCD group, activation in the PCC and the premotor/DLPFC was associated with greater pathological doubt. This finding is consistent with the observation that OCD patients often experience extreme doubt, even when memory performance is intact.

Solution structure of the SGTA dimerisation domain and investigation of its interactions with the ubiquitin-like domains of BAG6 and UBL4A.

BACKGROUND: The BAG6 complex resides in the cytosol and acts as a sorting point to target diverse hydrophobic protein substrates along their appropriate paths, including proteasomal degradation and ER membrane insertion. Composed of a trimeric complex of BAG6, TRC35 and UBL4A, the BAG6 complex is closely associated with SGTA, a co-chaperone from which it can obtain hydrophobic substrates. METHODOLOGY AND PRINCIPAL FINDINGS: SGTA consists of an N-terminal dimerisation domain (SGTA_NT), a central tetratricopeptide repeat (TPR) domain, and a glutamine rich region towards the C-terminus. Here we solve a solution structure of the SGTA dimerisation domain and use biophysical techniques to investigate its interaction with two different UBL domains from the BAG6 complex. The SGTA_NT structure is a dimer with a tight hydrophobic interface connecting two sets of four alpha helices. Using a combination of NMR chemical shift perturbation, isothermal titration calorimetry (ITC) and microscale thermophoresis (MST) experiments we have biochemically characterised the interactions of SGTA with components of the BAG6 complex, the ubiquitin-like domain (UBL) containing proteins UBL4A and BAG6. We demonstrate that the UBL domains from UBL4A and BAG6 directly compete for binding to SGTA at the same site. Using a combination of structural and interaction data we have implemented the HADDOCK protein-protein interaction docking tool to generate models of the SGTA-UBL complexes. SIGNIFICANCE: This atomic level information contributes to our understanding of the way in which hydrophobic proteins have their fate decided by the collaboration between SGTA and the BAG6 complex.

Musical obsessions: a comprehensive review of neglected clinical phenomena.

Intrusive musical imagery (IMI) consists of involuntarily recalled, short, looping fragments of melodies. Musical obsessions are distressing, impairing forms of IMI that merit investigation in their own right and, more generally, research into these phenomena may broaden our understanding of obsessive-compulsive disorder (OCD), which is phenomenologically and etiologically heterogeneous. We present the first comprehensive review of musical obsessions, based on the largest set of case descriptions ever assembled (N=96). Characteristics of musical obsessions are described and compared with normal IMI, musical hallucinations, and visual obsessional imagery. Assessment, differential diagnosis, comorbidity, etiologic hypotheses, and treatments are described. Musical obsessions may be under-diagnosed because they are not adequately assessed by current measures of OCD. Musical obsessions have been misdiagnosed as psychotic phenomena, which has led to ineffective treatment. Accurate diagnosis is important for appropriate treatment. Musical obsessions may respond to treatments that are not recommended for prototypic OCD symptoms.

Anterior cingulate cortex involvement in subclinical social anxiety.

We demonstrated differential activation in the anterior cingulate cortex (ACC) between subjects with high and low social anxiety in response to angry versus neutral faces. Activation in the ACC distinguished between facial expressions in the low, but not the high, anxious group. The ACC's role in threat processing is discussed.

The timing of exposure in clinic-based treatment for childhood anxiety disorders.

The present study examines treatment length and timing of exposure from two child anxiety disorders clinics. Data regarding symptoms and treatment characteristics for 28 youth were prospectively obtained through self, parent, and therapist report at each session. Information regarding length of treatment, timing of exposure initiation, and drop-out rates were compared with those obtained through efficacy and effectiveness trials of manualized treatment for anxious youth. Findings from the authors' clinical data revealed significantly shorter treatment duration with exposures implemented sooner than in the previous studies. Dropout rates were significantly higher than in the efficacy trial but comparable with the effectiveness trial. Outcome data from a subset of eight patients revealed large effect sizes. These findings suggest that effective treatment can be shorter and more focused on exposure than is often outlined in manuals and have important implications for outcome research and dissemination.

1H, 13C and 15N assignments of Sgt2 N-terminal dimerisation domain and its binding partner, Get5 Ubiquitin-like domain.

The first stage of the GET (guided entry of tail-anchored proteins) mechanism for tail-anchored (TA) membrane protein insertion is thought to occur when Sgt2 (small, glutamine-rich, tetratricopeptide repeat-containing protein 2) binds TA proteins upon their release from the ribosome. It sorts them and passes the majority over to a complex of Get5 and Get4 for transmission along the GET pathway and delivery to their membrane destination. Sgt2 is a 38 kDa protein consisting of three domains. The N-terminal domain effects tight dimerisation of the protein and is also the site for binding with the ubiquitin-like (UBL) domain of Get5. Here we have expressed and purified uniformly-(15)N/(13)C-labelled N-terminal Sgt2 (Sgt2_NT) and its binding partner, Get5 UBL domain (Get5_UBL) and assigned the backbone and side-chain resonances as a basis for structure solution of the individual components and, ultimately, the complex. This will provide detailed molecular insight into the early stages of the GET pathway.