Striatal morphology correlates with frontostriatal electrophysiological motor processing in Huntington's disease: an IMAGE-HD study.

Background: Huntington's disease (HD) causes progressive atrophy to the striatum, a critical node in frontostriatal circuitry. Maintenance of motor function is dependent on functional connectivity of these premotor, motor, and dorsolateral frontostriatal circuits, and structural integrity of the striatum itself. We aimed to investigate whether size and shape of the striatum as a measure of frontostriatal circuit structural integrity was correlated with functional frontostriatal electrophysiological neural premotor processing (contingent negative variation, CNV), to better understand motoric structure-function relationships in early HD.

Cortical inhibitory deficits in Huntington's disease are not influenced by gender.

Huntington's disease (HD) affects GABA-mediated inhibitory circuitry in the cortex. As there is evidence that sex hormones affect GABAergic function, we investigated whether gender modulates GABA-related pathophysiological changes in HD. Fifteen premanifest HD, 11 symptomatic HD and 16 healthy control participants were assessed with paired-pulse transcranial magnetic stimulation applied to the primary motor cortex.

Emotion Evaluation and Social Inference Impairments in Huntington's Disease.

Background: Huntington's disease (HD) is an inherited neurodegenerative disorder characterised by motor, cognitive and neuropsychiatric symptoms. Recent research has established that individuals with HD display reduced discrimination of emotional facial expressions and impaired higher-order social cognitive skills, including 'theory of mind'.

Objective: This study aimed to further characterise the emotion evaluation and theory of mind deficits in HD in an ecologically-valid context, and determine their impact on socially-relevant functional abilities.

Subjective sleep problems in Huntington's disease: A pilot investigation of the relationship to brain structure, neurocognitive, and neuropsychiatric function.

Subjective reports of sleep disturbance are a common feature of Huntington's disease (HD); however, there is limited research investigating the relationship between sleep problems with changes in brain and behaviour. This study aimed to investigate whether subjective reports of sleep problems in HD are associated with brain volume, neurocognitive decline, and neuropsychiatric symptoms. This retrospective pilot study used brain volume, neurocognitive and neuropsychiatric data from premanifest (pre-HD) and symptomatic HD (symp-HD).

A GABBR2 gene variant modifies pathophysiology in Huntington's disease.

Striatal degeneration in Huntington's disease (HD) causes changes in cortico-subcortical pathways. Transcranial magnetic stimulation (TMS) is a valuable tool for assessing pathophysiology within these pathways, yet has had limited application in HD. As cortico-subcortical pathways are largely mediated by GABA and dopamine receptor genes, understanding how these genes modulate neurophysiology in HD may provide new insights into how underlying pathology maps onto clinical phenotype.

Functional Brain Correlates of Neuropsychiatric Symptoms in Presymptomatic Huntington's Disease: The IMAGE-HD Study.

Background: Neuropsychiatric disturbances are common in Huntington's Disease (HD) and have been observed in gene-positive individuals several years prior to the onset of motor symptoms. The neural mechanism underpinning the development of neuropsychiatric problems in HD remain unclear.

Objective: To investigate whether neural activity during working memory is associated with neuropsychiatric symptoms in premanifest Huntington's Disease.

Multimodal imaging biomarkers in premanifest and early Huntington's disease: 30-month IMAGE-HD data.

Background: The discovery of potential disease-modifying therapies in a neurodegenerative condition like Huntington's disease depends on the availability of sensitive biomarkers that reflect decline across disease stages and that are functionally and clinically relevant.

Aims: To quantify macrostructural and microstructural changes in participants with premanifest and symptomatic Huntington's disease over 30 months, and to establish their functional and clinical relevance.

Method: Multimodal magnetic resonance imaging study measuring changes in macrostructural (volume) and microstructural (diffusivity) measures in 40 patients with premanifest Huntington's disease, 36 patients with symptomatic Huntington's disease and 36 healthy control participants over three testing sessions spanning 30 months.

Cortical inhibitory deficits in premanifest and early Huntington's disease.

Although progress has been made towards understanding the gross cortical and subcortical pathology of Huntington's disease (HD), there remains little understanding of the progressive pathophysiological changes that occur in the brain circuits underlying the disease. Transcranial magnetic stimulation (TMS) enables investigation of the functional integrity of cortico-subcortical pathways, yet it has not been widely applied in HD research to date. This study sought to characterise profiles of cortical excitability, including inhibition and facilitation, in groups of premanifest and symptomatic HD participants via the use of TMS.

Abnormal Electrophysiological Motor Responses in Huntington's Disease: Evidence of Premanifest Compensation.

Background: Huntington's disease (HD) causes progressive motor dysfunction through characteristic atrophy. Changes to neural structure begin in premanifest stages yet individuals are able to maintain a high degree of function, suggesting involvement of supportive processing during motor performance. Electroencephalography (EEG) enables the investigation of subtle impairments at the neuronal level, and possible compensatory strategies, by examining differential activation patterns.

Dual Task Performance May be a Better Measure of Cognitive Processing in Huntington's Disease than Traditional Attention Tests.

Background: Past research has found cancellation tasks to be reliable markers of cognitive decline in Huntington's disease (HD).

Objective: The aim of this study was to extend previous findings by adopting the use of a dual task paradigm that paired cancellation and auditory tasks.

Methods: We compared performance in 14 early stage HD participants and 14 healthy controls.

Characterising Upper Limb Movements in Huntington's Disease and the Impact of Restricted Visual Cues.

Background: Voluntary motor deficits are a common feature in Huntington's disease (HD), characterised by movement slowing and performance inaccuracies. This deficit may be exacerbated when visual cues are restricted.

Objective: To characterize the upper limb motor profile in HD with various levels of difficulty, with and without visual targets.

Iron accumulation in the basal ganglia in Huntington's disease: cross-sectional data from the IMAGE-HD study.

Objectives: To measure iron accumulation in the basal ganglia in Huntington's disease (HD) using quantitative susceptibility mapping (QSM), and to ascertain its relevance in terms of clinical and disease severity.

Methods: In this cross-sectional investigation, T2* weighted imaging was undertaken on 31 premanifest HD, 32 symptomatic HD and 30 control participants as part of the observational IMAGE-HD study. Group differences in iron accumulation were ascertained with QSM.

An open-label trial in Friedreich ataxia suggests clinical benefit with high-dose resveratrol, without effect on frataxin levels.

Friedreich ataxia (FRDA) is due to a triplet repeat expansion in FXN, resulting in deficiency of the mitochondrial protein frataxin. Resveratrol is a naturally occurring polyphenol, identified to increase frataxin expression in cellular and mouse models of FRDA and has anti-oxidant properties. This open-label, non-randomized trial evaluated the effect of two different doses of resveratrol on peripheral blood mononuclear cell (PBMC) frataxin levels over a 12-week period in individuals with FRDA.

Volumetric analysis of the hypothalamus in Huntington Disease using 3T MRI: the IMAGE-HD Study.

Huntington disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene. Non-motor symptoms and signs such as psychiatric disturbances, sleep problems and metabolic dysfunction are part of the disease manifestation. These aspects may relate to changes in the hypothalamus, an area of the brain involved in the regulation of emotion, sleep and metabolism.

Aggression in Huntington's disease: a systematic review of rates of aggression and treatment methods.

Aggression is commonly reported in individuals with Huntington's disease (HD). While correlating factors for aggression are often speculated about, features that are associated with, and contribute to, aggression in this population have not been clearly determined. This systematic review investigates rates of aggression and treatment options for aggression in HD.

Longitudinal change in white matter microstructure in Huntington's disease: The IMAGE-HD study.

Objective: To quantify 18-month changes in white matter microstructure in premanifest (pre-HD) and symptomatic Huntington's disease (symp-HD). To investigate baseline clinical, cognitive and motor symptoms that are predictive of white matter microstructural change over 18months.

Method: Diffusion tensor imaging (DTI) data were analyzed for 28 pre-HD, 25 symp-HD, and 27 controls scanned at baseline and after 18months.

Dual task performance in Huntington's disease: A comparison of choice reaction time tasks.

Objective: This study investigated whether dual tasks make disproportionately high demands in Huntington's disease (HD) compared with controls, and also tested the Multiple Resources Theory.

Method: Thirteen HD participants and 13 controls completed 2 dual task sets that varied in difficulty and complexity: Set 1 paired simple choice reaction time (RT) with digit forward, and Set 2 paired complex choice RT with digit backward.

Results: We found that HD participants were overall slower; however, although they maintained similar levels of accuracy in the simple choice RT tasks with controls, their accuracy decreased in the complex choice RT tasks.

Mutations in RAB39B cause X-linked intellectual disability and early-onset Parkinson disease with α-synuclein pathology.

Advances in understanding the etiology of Parkinson disease have been driven by the identification of causative mutations in families. Genetic analysis of an Australian family with three males displaying clinical features of early-onset parkinsonism and intellectual disability identified a ∼45 kb deletion resulting in the complete loss of RAB39B. We subsequently identified a missense mutation (c.

Effects of task difficulty during dual-task circle tracing in Huntington's disease.

Huntington's disease (HD) is associated with impairments in dual-task performance. Despite that, only a few studies have investigated dual-tasking in HD. We examined dual-task performance in 15 participants in the early stages of HD and 15 healthy controls.

A study of up to 12 years of follow-up of Friedreich ataxia utilising four measurement tools.

Objective: To explore the progression of Friedreich ataxia by analysing the change in scores of four clinical measures (the Friedreich Ataxia Rating Scale (FARS), the International Cooperative Ataxia Rating Scale (ICARS), the Functional Independence Measure (FIM) and the Modified Barthel Index (MBI)) over a period of up to 12 years, to ascertain the effects of clinical variables on performance of these measures, and to determine the most sensitive rating scale for measuring disease progression.

Methods: We measured the disease progression of up to 147 individuals against disease duration grouped into 5-year intervals. Additional subgroups were created to study the effects of the size of the smaller FXN intron 1 GAA repeat size (GAA1) and onset age on rating scale performance.

White matter connectivity reflects clinical and cognitive status in Huntington's disease.

Objective: To investigate structural connectivity and the relationship between axonal microstructure and clinical, cognitive, and motor functions in premanifest (pre-HD) and symptomatic (symp-HD) Huntington's disease.

Method: Diffusion tensor imaging (DTI) data were acquired from 35 pre-HD, 36 symp-HD, and 35 controls. Structural connectivity was mapped between 40 brain regions of interest using tractography.

Functional changes during working memory in Huntington's disease: 30-month longitudinal data from the IMAGE-HD study.

We characterized 30-month longitudinal change in functional activation and connectivity during working memory in premanifest (pre-HD) and symptomatic (symp-HD) Huntington's disease (HD). In a case-control longitudinal study (baseline, 18 months, and 30 months), we compared change in fMRI activity over time during working memory in 22 pre-HD, 11 symp-HD, and 20 control participants. Outcome measures were BOLD (blood-oxygen-level-dependent) activity during 1-BACK and 2-BACK working memory and functional connectivity between dorsolateral prefrontal cortex (DLPFC) and caudate.

Abnormal synchrony of resting state networks in premanifest and symptomatic Huntington disease: the IMAGE-HD study.

Background: Functional neural impairments have been documented in people with symptomatic Huntington disease (symp-HD) and in premanifest gene carriers (pre-HD). This study aimed to characterize synchrony in resting state cerebral networks in both pre-HD and symp-HD populations and to determine its association with disease burden and neurocognitive functions.

Methods: We acquired functional magnetic resonance imaging (fMRI) data from pre-HD, symp-HD and healthy control participants.

Cortisol and depression in pre-diagnosed and early stage Huntington's disease.

Hypothalamic-pituitary-adrenal (HPA) axis dysfunction and depression have both been shown to occur in Huntington's disease (HD) gene carriers prior to diagnosis (pre-HD) and in diagnosed HD patients. However, the relationship between HPA axis dysfunction and the severity of depressive symptomatology in pre-HD and early-HD has not been systematically examined, despite morning hypercortisolism being a characteristic feature of some subtypes of idiopathic depression. The aim of this study was to investigate whether HPA axis function is related to levels of depression in pre-HD and early-HD.