A Randomized Controlled Trial of Probiotics Targeting Gut Dysbiosis in Huntington's Disease.

BACKGROUND: Gastrointestinal symptoms are clinical features of Huntington's disease (HD), which adversely affect people's quality of life. We recently reported the first evidence of gut dysbiosis in HD gene expansion carriers (HDGECs). Here, we report on a randomized controlled clinical trial of a 6-week probiotic intervention in HDGECs. OBJECTIVE: The primary objective was to determine whether probiotics improved gut microbiome composition in terms of richness, evenness, structure, and diversity of functional pathways and enzymes. Exploratory objectives were to determine whether probiotic supplementation improved cognition, mood, and gastrointestinal symptoms. METHODS: Forty-one HDGECs, including 19 early manifest and 22 premanifest HDGECs were compared with 36 matched-healthy controls (HCs). Participants were randomly assigned probiotics or placebo and provided fecal samples at baseline and 6-week follow-up, which were sequenced using 16S-V3-V4 rRNA to characterize the gut microbiome. Participants completed a battery of cognitive tests and self-report questionnaires measuring mood and gastrointestinal symptoms. RESULTS: HDGECs had altered gut microbiome diversity when compared to HCs, indicating gut dysbiosis. Probiotic intervention did not ameliorate gut dysbiosis or have any effect on cognition, mood, or gastrointestinal symptoms. Gut microbiome differences between HDGECs and HCs were unchanged across time points, suggesting consistency of gut microbiome differences within groups. CONCLUSION: Despite the lack of probiotic effects in this trial, the potential utility of the gut as a therapeutic target in HD should continue to be explored given the clinical symptomology, gut dysbiosis, and positive results from probiotics and other gut interventions in similar neurodegenerative diseases.

Hippocampal and striatal volumes correlate with spatial memory impairment in Huntington's disease.

Spatial memory impairments are observed in people with Huntington's disease (HD), however, the domain of spatial memory has received little focus when characterizing the cognitive phenotype of HD. Spatial memory is traditionally thought to be a hippocampal-dependent function, while the neuropathology of HD centers on the striatum. Alongside spatial memory deficits in HD, recent neurocognitive theories suggest that a larger brain network is involved, including the striatum. We examined the relationship between hippocampal and striatal volumes and spatial memory in 36 HD gene expansion carriers, including premanifest (n = 24) and early manifest HD (n = 12), and 32 matched healthy controls. We assessed spatial memory with Paired Associates Learning, Rey-Osterrieth Complex Figure Test, and the Virtual House task, which assesses three components of spatial memory: navigation, object location, and plan drawing. Caudate nucleus, putamen, and hippocampal volumes were manually segmented on T1-weighted MR images. As expected, caudate nucleus and putamen volumes were significantly smaller in the HD group compared to controls, with manifest HD having more severe atrophy than the premanifest HD group. Hippocampal volumes did not differ significantly between HD and control groups. Nonetheless, on average, the HD group performed significantly worse than controls across all spatial memory tasks. The spatial memory components of object location and recall of figural and topographical drawings were associated with striatal and hippocampal volumes in the HD cohort. We provide a case to include spatial memory impairments in the cognitive phenotype of HD, and extend the neurocognitive picture of HD beyond its primary pathology within the striatum.

The Monash Autism-ADHD genetics and neurodevelopment (MAGNET) project design and methodologies: a dimensional approach to understanding neurobiological and genetic aetiology.

BACKGROUND: ASD and ADHD are prevalent neurodevelopmental disorders that frequently co-occur and have strong evidence for a degree of shared genetic aetiology. Behavioural and neurocognitive heterogeneity in ASD and ADHD has hampered attempts to map the underlying genetics and neurobiology, predict intervention response, and improve diagnostic accuracy. Moving away from categorical conceptualisations of psychopathology to a dimensional approach is anticipated to facilitate discovery of data-driven clusters and enhance our understanding of the neurobiological and genetic aetiology of these conditions. The Monash Autism-ADHD genetics and neurodevelopment (MAGNET) project is one of the first large-scale, family-based studies to take a truly transdiagnostic approach to ASD and ADHD. Using a comprehensive phenotyping protocol capturing dimensional traits central to ASD and ADHD, the MAGNET project aims to identify data-driven clusters across ADHD-ASD spectra using deep phenotyping of symptoms and behaviours; investigate the degree of familiality for different dimensional ASD-ADHD phenotypes and clusters; and map the neurocognitive, brain imaging, and genetic correlates of these data-driven symptom-based clusters. METHODS: The MAGNET project will recruit 1,200 families with children who are either typically developing, or who display elevated ASD, ADHD, or ASD-ADHD traits, in addition to affected and unaffected biological siblings of probands, and parents. All children will be comprehensively phenotyped for behavioural symptoms, comorbidities, neurocognitive and neuroimaging traits and genetics. CONCLUSION: The MAGNET project will be the first large-scale family study to take a transdiagnostic approach to ASD-ADHD, utilising deep phenotyping across behavioural, neurocognitive, brain imaging and genetic measures.

Feasibility and initial validation of 'HD-Mobile', a smartphone application for remote self-administration of performance-based cognitive measures in Huntington's disease.

OBJECTIVE: Smartphone-based cognitive assessment measures allow efficient, rapid, and convenient collection of cognitive datasets. Establishment of feasibility and validity is essential for the widespread use of this approach. We describe a novel smartphone application (HD-Mobile) that includes three performance-based cognitive tasks with four key outcome measures, for use with Huntington's disease (HD) samples. We describe known groups and concurrent validity, test-retest reliability, sensitivity, and feasibility properties of the tasks. METHODS: Forty-two HD CAG-expanded participants (20 manifest, 22 premanifest) and 28 healthy controls completed HD-Mobile cognitive tasks three times across an 8-day period, on days 1, 4, and 8. A subsample of participants had pen-and-paper cognitive task data available from their most recent assessment from their participation in a separate observational longitudinal study, Enroll-HD. RESULTS: Manifest-HD participants performed worse than healthy controls for three of four HD-Mobile cognitive measures, and worse than premanifest-HD participants for two of four measures. We found robust test-retest reliability for manifest-HD participants (ICC = 0.71-0.96) and with some exceptions, in premanifest-HD (ICC = 0.52-0.96) and healthy controls (0.54-0.96). Correlations between HD-Mobile and selected Enroll-HD cognitive tasks were mostly medium to strong (r = 0.36-0.68) as were correlations between HD-Mobile cognitive tasks and measures of expected disease progression and motor symptoms for the HD CAG-expanded participants (r = - 0.34 to - 0.54). CONCLUSIONS: Results indicated robust known-groups, test-retest, concurrent validity, and sensitivity of HD-Mobile cognitive tasks. The study demonstrates the feasibility and utility of HD-Mobile for conducting convenient, frequent, and potentially ongoing assessment of HD samples without the need for in-person assessment.

Gut dysbiosis in Huntington's disease: associations among gut microbiota, cognitive performance and clinical outcomes.

Huntington's disease is characterized by a triad of motor, cognitive and psychiatric impairments, as well as unintended weight loss. Although much of the research has focused on cognitive, motor and psychiatric symptoms, the extent of peripheral pathology and the relationship between these factors, and the core symptoms of Huntington's disease, are relatively unknown. Gut microbiota are key modulators of communication between the brain and gut, and alterations in microbiota composition (dysbiosis) can negatively affect cognition, behaviour and affective function, and may be implicated in disease progression. Furthermore, gut dysbiosis was recently reported in Huntington's disease transgenic mice. Our main objective was to characterize the gut microbiome in people with Huntington's disease and determine whether the composition of gut microbiota are significantly related to clinical indicators of disease progression. We compared 42 Huntington's disease gene expansion carriers, including 19 people who were diagnosed with Huntington's disease (Total Functional Capacity > 6) and 23 in the premanifest stage, with 36 age- and gender-matched healthy controls. Participants were characterized clinically using a battery of cognitive tests and using results from 16S V3 to V4 rRNA sequencing of faecal samples to characterize the gut microbiome. For gut microbiome measures, we found significant differences in the microbial communities (beta diversity) based on unweighted UniFrac distance (P = 0.001), as well as significantly lower alpha diversity (species richness and evenness) between our combined Huntington's disease gene expansion carrier group and healthy controls (P = 0.001). We also found major shifts in the microbial community structure at Phylum and Family levels, and identified functional pathways and enzymes affected in our Huntington's disease gene expansion carrier group. Within the Huntington's disease gene expansion carrier group, we also discovered associations among gut bacteria, cognitive performance and clinical outcomes. Overall, our findings suggest an altered gut microbiome in Huntington's disease gene expansion carriers. These results highlight the importance of gut biomarkers and raise interesting questions regarding the role of the gut in Huntington's disease, and whether it may be a potential target for future therapeutic intervention.

'Real-life' hippocampal-dependent spatial memory impairments in Huntington's disease.

Hippocampal-dependent spatial memory impairments are seen in Huntington's disease animal models. Similar impairments were recently reported in Huntington's disease participants on analogous spatial memory tasks (e.g., virtual Morris Water Maze), however, these tasks do not translate well to the range of functions involved in day-to-day spatial cognition. In this study we examined 'real-life' hippocampal-dependent spatial memory in Huntington's disease participants. We studied premanifest Huntington's disease (N = 24), early manifest Huntington's disease (N = 14), and matched healthy controls (N = 33) with a virtual environment, which demanded spatial memory function on three levels: navigation, object location, and plan drawing. To examine the case for hippocampal-dependent spatial memory more closely, we compared the performance of our Huntington's disease participants to that of a group of temporal lobe epilepsy patients (N = 30) who were previously tested on the virtual environment. Spatial memory performance was also compared to two common neuropsychological tests of spatial cognition, the Paired Associates Learning from the Cambridge Neuropsychological Automated Test Battery, and the Rey-Osterrieth Complex Figure Test. People with early manifest Huntington's disease were impaired across all spatial memory tasks. Premanifest Huntington's disease participants were most notably impaired on the object location measure of the virtual environment, which is heavily dependent on hippocampal function, but showed no such impairments on the Paired Associates Learning or the Rey-Osterrieth Complex Figure Test. Object location memory and navigation performance did not differ between people with Huntington's disease and temporal lobe epilepsy. Aligned with studies in Huntington's disease animal models, 'real-life' spatial memory is impaired in people with Huntington's disease prior to clinical diagnosis. This alignment has important implications for testing treatments for Huntington's disease. From the standpoint of neurodegeneration, the dependence of our spatial memory measures on hippocampal function extends the focus of cognitive assessment research in Huntington's disease beyond its primary pathology within the striato-frontal circuit.

Families Affected by Huntington's Disease Report Difficulties in Communication, Emotional Involvement, and Problem Solving.

BACKGROUND: Family functioning in Huntington's disease (HD) is known from previous studies to be adversely affected. However, which aspects of family functioning are disrupted is unknown, limiting the empirical basis around which to create supportive interventions. OBJECTIVE: The aim of the current study was to assess family functioning in HD families. METHODS: We assessed family functioning in 61 participants (38 HD gene-expanded participants and 23 family members) using the McMaster Family Assessment Device (FAD; Epstein, Baldwin and Bishop, 1983), which provides scores for seven domains of functioning: Problem Solving; Communication; Affective Involvement; Affective Responsiveness; Behavior Control; Roles; and General Family Functioning. RESULTS: The most commonly reported disrupted domain for HD participants was Affective Involvement, which was reported by 39.5% of HD participants, followed closely by General Family Functioning (36.8%). For family members, the most commonly reported dysfunctional domains were Affective Involvement and Communication (both 52.2%). Furthermore, symptomatic HD participants reported more disruption to Problem Solving than pre-symptomatic HD participants. In terms of agreement between pre-symptomatic and symptomatic HD participants and their family members, all domains showed moderate to very good agreement. However, on average, family members rated Communication as more disrupted than their HD affected family member. CONCLUSION: These findings highlight the need to target areas of emotional engagement, communication skills and problem solving in family interventions in HD.

Cognitive interventions to enhance neural compensation in Huntington's disease.

In Huntington's disease (HD), there is growing evidence of neural compensation during neurodegeneration, and that these processes might be modifiable by environmental factors. Cognitive intervention to improve brain function has been trialled only to a very limited extent in HD; however, it has shown promise in other neurodegenerative diseases. In this review, we discuss the evidence for the use of cognitive intervention to boost neural compensation in HD, and find it has potential to delay clinical decline, particularly if applied early in the disease process. Randomized controlled trials of cognitive intervention in HD should be implemented as a next step to gauging the efficacy of this approach to improve outcomes for those with the HD gene.