Whole-Brain Connectivity in a Large Study of Huntington's Disease Gene Mutation Carriers and Healthy Controls

Objective: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. Neurofilament light protein (NfL) is correlated with clinical severity of HD but relative data are the lack in the Chinese population. Reactive astrocytes are related to HD pathology, which predicts their potential to be a biomarker in HD progression. Our aim was to discuss the role of blood glial fibrillary acidic protein (GFAP) to evaluate clinical severity in patients with HD.Methods: Fifty-seven HD mutation carriers (15 premanifest HD, preHD, and 42 manifest HD) and 26 healthy controls were recruited. Demographic data and clinical severity assessed with the internationally Unified Huntington's Disease Rating Scale (UHDRS) were retrospectively analyzed. Plasma NfL and GFAP were quantified with an ultra-sensitive single-molecule (Simoa, Norcross, GA, USA) technology. We explored their consistency and their correlation with clinical severity.Results: Compared with healthy controls, plasma NfL (p < 0.0001) and GFAP (p < 0.001) were increased in Chinese HD mutation carriers, and they were linearly correlated with each other (r = 0.612, p < 0.001). They were also significantly correlated with disease burden, Total Motor Score (TMS) and Total Functional Capacity (TFC). The scores of Stroop word reading, symbol digit modalities tests, and short version of the Problem Behaviors Assessments (PBAs) for HD were correlated with plasma NfL but not GFAP. Compared with healthy controls, plasma NfL has been increased since stage 1 but plasma GFAP began to increase statistically in stage 2.Conclusions: Plasma GFAP was correlated with plasma NfL, disease burden, TMS, and TFC in HD mutation carriers. Plasma GFAP may have potential to be a sensitive biomarker for evaluating HD progression.

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Arithmetic Word-Problem Solving as Cognitive Marker of Progression in Pre-Manifest and Manifest Huntington’s Disease

Journal of Huntington s Disease ◽

10.3233/jhd-210480 ◽

2021 ◽

pp. 1-10

Author(s):

Andrea Horta-Barba ◽

Saul Martinez-Horta ◽

Jesús Perez-Perez ◽

Frederic Sampedro ◽

Natascia de Lucia ◽

...

Keyword(s):

Problem Solving ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Gene Mutation ◽

Word Problem ◽

Arithmetic Task ◽

Word Problem Solving ◽

Mutation Carriers ◽

Time To Diagnosis ◽

Arithmetic Word Problem

Background: Arithmetic word-problem solving depends on the interaction of several cognitive processes that may be affected early in the disease in gene-mutation carriers for Huntington’s disease (HD). Objective: Our goal was to examine the pattern of performance of arithmetic tasks in premanifest and manifest HD, and to examine correlations between arithmetic task performance and other neuropsychological tasks. Methods: We collected data from a multicenter cohort of 165 HD gene-mutation carriers. The sample consisted of 31 premanifest participants: 16 far-from (>12 years estimated time to diagnosis; preHD-A) and 15 close-to (≤12 years estimated time to diagnosis; preHD-B), 134 symptomatic patients (early-mild HD), and 37 healthy controls (HC). We compared performance between groups and explored the associations between arithmetic word-problem solving and neuropsychological and clinical variables. Results: Total arithmetic word-problem solving scores were lower in preHD-B patients than in preHD-A (p < 0.05) patients and HC (p < 0.01). Early-mild HD patients had lower scores than preHD patients (p < 0.001) and HC (p < 0.001). Compared to HC, preHD and early-mild HD participants made more errors as trial complexity increased. Moreover, arithmetic word-problem solving scores were significantly associated with measures of global cognition (p < 0.001), frontal-executive functions (p < 0.001), attention (p < 0.001) and visual working memory (p < 0.001), mental rotation (p < 0.001), and confrontation naming (p < 0.05). Conclusion: Arithmetic word-problem solving is affected early in the course of HD and is related to deficient processes in frontal-executive and mentalizing-related processes.

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A32 Metabolic capacity and mitochondrial respiration at rest and after physical exercise in huntington’s disease mutation carriers and healthy controls

10.1136/jnnp-2018-ehdn.30 ◽

2018 ◽

Author(s):

KS Lindenberg ◽

U Schumann ◽

F Hummes ◽

GB Landwehrmeyer ◽

J Steinacker ◽

...

Keyword(s):

Physical Exercise ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Mitochondrial Respiration ◽

Healthy Controls ◽

Metabolic Capacity ◽

Disease Mutation ◽

Mutation Carriers

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

Brain Communications ◽

10.1093/braincomms/fcaa110 ◽

2020 ◽

Vol 2 (2) ◽

Cited By ~ 3

Author(s):

Cory I Wasser ◽

Emily-Clare Mercieca ◽

Geraldine Kong ◽

Anthony J Hannan ◽

Sonja J McKeown ◽

...

Keyword(s):

Gut Microbiota ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Disease Progression ◽

Cognitive Performance ◽

Gut Microbiome ◽

Disease Gene ◽

Healthy Controls ◽

Gut Dysbiosis ◽

Gene Expansion

Abstract 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.

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Mild Cognitive Impairment as an Early Landmark in Huntington's Disease

Frontiers in Neurology ◽

10.3389/fneur.2021.678652 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ying Zhang ◽

Junyi Zhou ◽

Carissa R. Gehl ◽

Jeffrey D. Long ◽

Hans Johnson ◽

...

Keyword(s):

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Gene Mutation ◽

Single Domain ◽

Disease Stage ◽

Mutation Carriers ◽

Prospective Longitudinal ◽

Hd Gene

As one of the clinical triad in Huntington's disease (HD), cognitive impairment has not been widely accepted as a disease stage indicator in HD literature. This work aims to study cognitive impairment thoroughly for prodromal HD individuals with the data from a 12-year observational study to determine whether Mild Cognitive Impairment (MCI) in HD gene-mutation carriers is a defensible indicator of early disease. Prodromal HD gene-mutation carriers evaluated annually at one of 32 worldwide sites from September 2002 to April 2014 were evaluated for MCI in six cognitive domains. Linear mixed-effects models were used to determine age-, education-, and retest-adjusted cut-off values in cognitive assessment for MCI, and then the concurrent and predictive validity of MCI was assessed. Accelerated failure time (AFT) models were used to determine the timing of MCI (single-, two-, and multiple-domain), and dementia, which was defined as MCI plus functional loss. Seven hundred and sixty-eight prodromal HD participants had completed all six cognitive tasks, had MRI, and underwent longitudinal assessments. Over half (i.e., 54%) of the participants had MCI at study entry, and half of these had single-domain MCI. Compared to participants with intact cognitive performances, prodromal HD with MCI had higher genetic burden, worsened motor impairment, greater brain atrophy, and a higher likelihood of estimated HD onset. Prospective longitudinal study of those without MCI at baseline showed that 48% had MCI in subsequent visits and data visualization suggested that single-domain MCI, two-domain MCI, and dementia represent appropriate cognitive impairment staging for HD gene-mutation carriers. Findings suggest that MCI represents an early landmark of HD and may be a sensitive enrichment variable or endpoint for prodromal clinical trials of disease modifying therapeutics.

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