Neuroimaging is increasingly being included in clinical trials of Huntington's disease (HD) for a wide range of purposes from participant selection and safety monitoring, through to demonstration of disease modification. Selection of the appropriate modality and associated analysis tools requires careful consideration. On behalf of the EHDN Imaging Working Group, we present current opinion on the utility and future prospects for inclusion of neuroimaging in HD trials.
View Article and Find Full Text PDFBackground: Whole-brain longitudinal diffusion studies are crucial to examine changes in structural connectivity in neurodegeneration. Here, we investigated the longitudinal alterations in white matter (WM) microstructure across the timecourse of Huntington's disease (HD).
Methods: We examined changes in WM microstructure from premanifest to early manifest disease, using data from two cohorts with different disease burden.
An important step towards the development of treatments for cognitive impairment in ageing and neurodegenerative diseases is to identify genetic and environmental modifiers of cognitive function and understand the mechanism by which they exert an effect. In Huntington's disease, the most common autosomal dominant dementia, a small number of studies have identified intellectual enrichment, i.e.
View Article and Find Full Text PDFIntroduction: Drug development for neurodegenerative diseases such as Friedreich's ataxia (FRDA) is limited by a lack of validated, sensitive biomarkers of pharmacodynamic response in affected tissue and disease progression. Studies employing neuroimaging measures to track FRDA have thus far been limited by their small sample sizes and limited follow up. TRACK-FA, a longitudinal, multi-site, and multi-modal neuroimaging natural history study, aims to address these shortcomings by enabling better understanding of underlying pathology and identifying sensitive, clinical trial ready, neuroimaging biomarkers for FRDA.
View Article and Find Full Text PDFUpregulation of functional network connectivity in the presence of structural degeneration is seen in the premanifest stages of Huntington's disease (preHD) 10-15 years from clinical diagnosis. However, whether widespread network connectivity changes are seen in gene carriers much further from onset has yet to be explored. We characterized functional network connectivity throughout the brain and related it to a measure of disease pathology burden (CSF neurofilament light, NfL) and measures of structural connectivity in asymptomatic gene carriers, on average 24 years from onset.
View Article and Find Full Text PDFReal-time fMRI neurofeedback is an increasingly popular neuroimaging technique that allows an individual to gain control over his/her own brain signals, which can lead to improvements in behavior in healthy participants as well as to improvements of clinical symptoms in patient populations. However, a considerably large ratio of participants undergoing neurofeedback training do not learn to control their own brain signals and, consequently, do not benefit from neurofeedback interventions, which limits clinical efficacy of neurofeedback interventions. As neurofeedback success varies between studies and participants, it is important to identify factors that might influence neurofeedback success.
View Article and Find Full Text PDFBiol Psychiatry Cogn Neurosci Neuroimaging
September 2021
Background: In this study, we asked whether differences in striatal activity during a reinforcement learning (RL) task with gain and loss domains could be one of the earliest functional imaging features associated with carrying the Huntington's disease (HD) gene. Based on previous work, we hypothesized that HD gene carriers would show either neural or behavioral asymmetry between gain and loss learning.
Methods: We recruited 35 HD gene carriers, expected to demonstrate onset of motor symptoms in an average of 26 years, and 35 well-matched gene-negative control subjects.
Background: Pathological processes in Huntington's disease (HD) begin many years prior to symptom onset. Recently we demonstrated that in a premanifest cohort approximately 24 years from predicted disease onset, despite intact function, there was evidence of subtle neurodegeneration. Here, we use novel imaging techniques to determine whether macro- and micro-structural changes can be detected across the whole-brain in the same cohort.
View Article and Find Full Text PDFObjectives: Cognitive flexibility, which is key for adaptive decision-making, engages prefrontal cortex (PFC)-striatal circuitry and is impaired in both manifest and premanifest Huntington's disease (pre-HD). The aim of this study was to examine cognitive flexibility in a far from onset pre-HD cohort to determine whether an early impairment exists and if so, whether fronto-striatal circuits were associated with this deficit.
Methods: In the present study, we examined performance of 51 pre-HD participants (mean age=29.
Non-invasive methods, such as neurofeedback training, could support cognitive symptom management in Huntington's disease by targeting brain regions whose function is impaired. The aim of our single-blind, sham-controlled study was to collect rigorous evidence regarding the feasibility of neurofeedback training in Huntington's disease by examining two different methods, activity and connectivity real-time functional MRI neurofeedback training. Thirty-two Huntington's disease gene-carriers completed 16 runs of neurofeedback training, using an optimized real-time functional MRI protocol.
View Article and Find Full Text PDFNeurofeedback training has been shown to influence behavior in healthy participants as well as to alleviate clinical symptoms in neurological, psychosomatic, and psychiatric patient populations. However, many real-time fMRI neurofeedback studies report large inter-individual differences in learning success. The factors that cause this vast variability between participants remain unknown and their identification could enhance treatment success.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
September 2019
Human behavior is surprisingly variable, even when facing the same problem under identical circumstances. A prominent example is risky decision making. Economic theories struggle to explain why humans are so inconsistent.
View Article and Find Full Text PDFAlthough the measurement of ankle-brachial index (ABI) is considered a fundamental skill in assessment and diagnosis of peripheral arterial disease and a predictive tool for cardiovascular events, real-world practice shows that the experience of many health professionals is far from ideal. Not only teaching and practice of ABI measurement in undergraduate medical curricula are limited but various mistakes in the process of calculation, estimation, and interpretation of ABI results in the postgraduate practice have also been documented. Because vascular surgery is a core subject in our medical school, we deal with the difficulties and challenges that undergraduate medical students and nurses face to measure and comprehend ABI.
View Article and Find Full Text PDFA high incidence of hemangiosarcoma (HSA) was observed in mice treated for 2 years with siponimod, a sphingosine-1-phosphate receptor 1 (S1P1) functional antagonist, while no such tumors were observed in rats under the same treatment conditions. In 3-month rat (90 mg/kg/day) and 9-month mouse (25 and 75 mg/kg/day) in vivo mechanistic studies, vascular endothelial cell (VEC) activation was observed in both species, but VEC proliferation and persistent increases in circulating placental growth factor 2 (PLGF2) were only seen in the mouse. In mice, these effects were sustained over the 9-month study duration, while in rats increased mitotic gene expression was present at day 3 only and PLGF2 was induced only during the first week of treatment.
View Article and Find Full Text PDFCognitive impairment is common amongst many neurodegenerative movement disorders such as Huntington's disease (HD) and Parkinson's disease (PD) across multiple domains. There are many tasks available to assess different aspects of this dysfunction, however, it is imperative that these show high test-retest reliability if they are to be used to track disease progression or response to treatment in patient populations. Moreover, in order to ensure effects of practice across testing sessions are not misconstrued as clinical improvement in clinical trials, tasks which are particularly vulnerable to practice effects need to be highlighted.
View Article and Find Full Text PDFNovel methods that stimulate neuroplasticity are increasingly being studied to treat neurological and psychiatric conditions. We sought to determine whether real-time fMRI neurofeedback training is feasible in Huntington's disease (HD), and assess any factors that contribute to its effectiveness. In this proof-of-concept study, we used this technique to train 10 patients with HD to volitionally regulate the activity of their supplementary motor area (SMA).
View Article and Find Full Text PDFWe lack a mechanistic explanation for the stereotyped pattern of white matter loss seen in Huntington's disease (HD). While the earliest white matter changes are seen around the striatum, within the corpus callosum, and in the posterior white matter tracts, the order in which these changes occur and why these white matter connections are specifically vulnerable is unclear. Here, we use diffusion tractography in a longitudinal cohort of individuals yet to develop clinical symptoms of HD to identify a hierarchy of vulnerability, where the topological length of white matter connections between a brain area and its neighbors predicts the rate of atrophy over 24 months.
View Article and Find Full Text PDFIn pre-clinical Huntington's disease, normal behaviour is maintained despite neurodegeneration, suggesting a mechanism of compensation. Gregory, Long . present two mathematical models of compensation over time and their operationalisation for neuroimaging.
View Article and Find Full Text PDFAnn Clin Transl Neurol
February 2017
Objectives: The distribution of pathology in neurodegenerative disease can be predicted by the organizational characteristics of white matter in healthy brains. However, we have very little evidence for the impact these pathological changes have on brain function. Understanding any such link between structure and function is critical for understanding how underlying brain pathology influences the progressive behavioral changes associated with neurodegeneration.
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