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.

Racial Differences in the Presentation and Progression of Huntington's Disease.

BACKGROUND: Huntington's disease (HD) is an autosomal dominant neurodegenerative disease that predominantly impacts a Caucasian population, but few efforts have explored racial differences in presentation and progression. OBJECTIVE: The aim was to assess the presentation and progression of HD across race groups using the Enroll-HD longitudinal observational study. METHODS: We applied propensity score matching for cytosine-adenine-guanine age product score, and age, to identify White, Hispanic, Asian, and Black participants from the Enroll-HD database. We compared clinical presentations at baseline, and progression over time, using White participants as a control cohort. RESULTS: Black participants were more severe at baseline across all clinical measures. No significant differences in progression were observed between race groups. CONCLUSIONS: We consider the factors driving clinical differences at baseline for Black participants. Our data emphasize the necessary improvement in underrepresented minority recruitment for studies of rare diseases. © 2023 International Parkinson and Movement Disorder Society.

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.

Interactions between the colonic transcriptome, metabolome, and microbiome in mouse models of obesity-induced intestinal cancer.

Obesity is a significant risk factor for colorectal cancer (CRC); however, the relative contribution of high-fat (HF) consumption and excess adiposity remains unclear. It is becoming apparent that obesity perturbs both the intestinal microbiome and metabolome, and each has the potential to induce protumorigenic changes in the epithelial transcriptome. The physiological consequences and the degree to which these different biologic systems interact remain poorly defined. To understand the mechanisms by which obesity drives colonic tumorigenesis, we profiled the colonic epithelial transcriptome of HF-fed and genetically obese (DbDb) mice with a genetic predisposition to intestinal tumorigenesis (Apc(1638N)); 266 and 584 genes were differentially expressed in the colonic mucosa of HF and DbDb mice, respectively. These genes mapped to pathways involved in immune function, and cellular proliferation and cancer. Furthermore, Akt was central within the networks of interacting genes identified in both gene sets. Regression analyses of coexpressed genes with the abundance of bacterial taxa identified three taxa, previously correlated with tumor burden, to be significantly correlated with a gene module enriched for Akt-related genes. Similarly, regression of coexpressed genes with metabolites found that adenosine, which was negatively associated with inflammatory markers and tumor burden, was also correlated with a gene module enriched with Akt regulators. Our findings provide evidence that HF consumption and excess adiposity result in changes in the colonic transcriptome that, although distinct, both appear to converge on Akt signaling. Such changes could be mediated by alterations in the colonic microbiome and metabolome.

S-adenosylmethionine mediates inhibition of inflammatory response and changes in DNA methylation in human macrophages.

S-adenosylmethionine (SAM), the unique methyl donor in DNA methylation, has been shown to lower lipopolysaccharide (LPS)-induced expression of the proinflammatory cytokine TNF-α and increase the expression of the anti-inflammatory cytokine IL-10 in macrophages. The aim of this study was to assess whether epigenetic mechanisms mediate the anti-inflammatory effects of SAM. Human monocytic THP1 cells were differentiated into macrophages and treated with 0, 500, or 1,000 µmol/l SAM for 24 h, followed by stimulation with LPS. TNFα and IL-10 expression levels were measured by real-time PCR, cellular concentrations of SAM and S-adenosylhomocysteine (SAH), a metabolite of SAM, were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and DNA methylation was measured with LC-MS/MS and microarrays. Relative to control (0 µmol/l SAM), treatment with 500 µmol/l SAM caused a significant decrease in TNF-α expression (-45%, P < 0.05) and increase in IL-10 expression (+77%, P < 0.05). Treatment with 1,000 µmol/l SAM yielded no significant additional benefits. Relative to control, 500 µmol/l SAM increased cellular SAM concentrations twofold without changes in SAH, and 1,000 µmol/l SAM increased cellular SAM sixfold and SAH fourfold. Global DNA methylation increased 7% with 500 µmol/l SAM compared with control. Following treatment with 500 µmol/l SAM, DNA methylation microarray analysis identified 765 differentially methylated regions associated with 918 genes. Pathway analysis of these genes identified a biological network associated with cardiovascular disease, including a subset of genes that were differentially hypomethylated and whose expression levels were altered by SAM. Our data indicate that SAM modulates the expression of inflammatory genes in association with changes in specific gene promoter DNA methylation.

Alterations in Cerebrospinal Fluid Urea Occur in Late Manifest Huntington's Disease.

Background: Huntington's disease (HD) is a neurodegenerative disorder caused by expanded cytosine-adenine-guanine (CAG) repeats in the Huntingtin gene, resulting in the production of mutant huntingtin proteins (mHTT). Previous research has identified urea as a key metabolite elevated in HD animal models and postmortem tissues of HD patients. However, the relationship between disease course and urea elevations, along with the molecular mechanisms responsible for these disturbances remain unknown. Objective: To better understand the molecular disturbances and timing of urea cycle metabolism across different stages in HD. Methods: We completed a global metabolomic profile of cerebrospinal fluid (CSF) from individuals who were at several stages of disease: pre-manifest (PRE), manifest (MAN), and late manifest (LATE) HD participants, and compared to controls. Results: Approximately 500 metabolites were significantly altered in PRE participants compared to controls, although no significant differences in CSF urea or urea metabolites were observed. CSF urea was significantly elevated in LATE participants only. There were no changes in the urea metabolites citrulline, ornithine, and arginine. Conclusions: Overall, our study confirms that CSF elevations occur late in the HD course, and these changes may reflect accumulating deficits in cellular energy metabolism.

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.

Koolen-de Vries Syndrome: a journey from diagnosis to treatments.

The Koolen-de Vries Syndrome Foundation was founded in 2013 with the mission to educate, increase awareness, promote research and develop treatments for individuals living with Koolen-de Vries Syndrome (KdVS) and their families. With this aim, the foundation has focused on: developing scientific resources through patient cell and animal models, providing seed funding to basic and clinical researchers, establishing a natural history study of KdVS and increasing patient engagement. Projects have been prioritized across these areas of focus with an emphasis on expanding international research on KdVS, supporting translational research, establishing an international natural history study and conducting studies to assess patient priorities. With the incredible growth amongst our research and patient community in the last decade, our goal is to have our first clinical trial for KdVS in 2026.

Koolen de-Vries Syndrome: a journey from diagnosis to treatments The Koolen-de Vries Syndrome Foundation ('KdVSF') was founded in 2013 with the mission to develop treatments for all individuals diagnosed with KdVS. With this aim, we have focused on several research priorities for our community: developing cell and animal models for KdVS for our researchers to utilize for experiments, providing research grants to KdVS basic and clinical researchers, establishing a natural history study of KdVS and increasing patient engagement and diversity. The KdVS research and patient community has expanded tremendously over the last decade, and there is growing excitement over the possible treatments currently being investigated amongst KdVS researchers. With our current focus on translational research and research aimed at identifying treatment strategies in KdVS patients, our goal is to have our first clinical trial for KdVS in late 2026.

Coping with Huntington's Disease in Patients and At-Risk Individuals.

Background: Huntington's disease (HD) presents patients and individuals at risk for HD with significant levels of stress. However, relatively little research has examined how individuals cope with stress related to the disease or the association of specific coping strategies with psychological symptoms. Objective: This study examined the ways in which HD patients and at-risk individuals cope with HD-related stress using a control-based model of coping and the association of coping strategies with symptoms of depression and anxiety. Methods: HD patients (n = 49) and at-risk individuals (n = 76) completed the Responses to Stress Questionnaire - Huntington's Disease Version to assess coping strategies in response to HD-related stress, as well as standardized measures of depression and anxiety symptoms. Patient health records were accessed to obtain information related to disease characteristics. Results: Patients and at-risk individuals reported using comparable levels of primary control coping, secondary control coping, and disengagement coping strategies. In linear regression analyses, only secondary control coping was significantly associated with lower depression (ß= -0.62, p < 0.001) and anxiety (ß= -0.59, p < 0.001) symptoms in patients and at-risk individuals (ß= -0.55, p < 0.001 and ß= -0.50, p < 0.001, respectively). Conclusions: Secondary control coping may be beneficial for both HD patients and at-risk individuals. Future research using the control-based model of coping in longitudinal studies with the HD population is needed, and future interventions could test the effects of cognitive reframing and acceptance as coping strategies for families affected by HD.

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.