Journal of Huntington's disease最新文献

Huntington's disease (HD) is a fatal neurodegenerative disorder characterized by progressive motor, cognitive, and psychiatric symptoms. Research efforts to understand and treat the disease have historically focused on neuronal pathology, but growing evidence underscores the critical role of oligodendrocytes in its pathogenesis. This review synthesizes recent findings on oligodendroglial dysfunction in HD, showing that white matter abnormalities arise early in disease progression, often preceding gray matter changes and clinical symptoms. Neuroimaging and postmortem studies reveal significant white matter atrophy, myelin breakdown, and impaired oligodendrocyte maturation in both patients and animal models. The myelination response to environmental factors is also altered in HD, suggesting impaired white matter plasticity in the disease. At the molecular level, mutant huntingtin disrupts oligodendrocyte function through transcriptional dysregulation of myelin genes, epigenetic modifications involving PRC2 and REST, altered lipid metabolism, thiamine pathway dysfunction, and aberrant BDNF signaling. Key oligodendroglial transcriptional regulators such as MYRF and TCF7L2 are compromised in HD, leading to defective myelination and reduced metabolic support for neurons. Recognizing the role of these mechanisms provides potential biomarkers for early detection and therapeutic targets aimed at preserving both neuronal and glial function in HD.

Microglia, the resident immune cells of the central nervous system, play a pivotal role in the response to Huntington's disease (HD) pathology. Through both cell-autonomous mechanisms and exposure to external pathogenic stimuli, microglia transition from a resting to an activated state, producing pro-inflammatory cytokines and chemokines that mediate inflammation. While this inflammatory response attempts to have a neuroprotective compensatory effect, chronic microglial activation exacerbates neuroinflammation, neurodegeneration and contributes to disease progression. Evidence from postmortem analyses and neuroimaging studies indicates that activated microglia are present in various stages of HD, correlating with neuronal degeneration and clinical symptoms. Enhanced microglial activation has been identified as an early predictor of disease onset, particularly in premanifest HD, highlighting the potential of targeting microglial pathways for therapeutic interventions. This review explores microglia's dual role in HD pathophysiology, exploring their contributions to both neuroinflammation and neuroprotection. It also examines recent advances in clinical trials aimed at modulating microglial activity, paving the way for novel therapeutic strategies to alter disease progression and improve patient outcomes.

Astrocytes are key elements for synapse development and function. Several astrocytic dysfunctions contribute to the pathophysiology of various neurodegenerative disorders, including Huntington's disease (HD), an autosomal-dominant neurodegenerative disorder that is characterized by motor and cognitive defects with behavioral/psychiatric disturbances. One dysfunction in HD related to astrocytes is reduced cholesterol synthesis, leading to a decreased availability of local cholesterol for synaptic activity. This review describes the specific role of astrocytes in the brain local cholesterol synthesis and presents evidence supporting a defective astrocyte-neuron cholesterol crosstalk in HD, by focusing on SREBP-2, the transcription factor that regulates the majority of genes involved in the cholesterol biosynthetic pathway. The emerging coordination of SREBP-2 with other physiological processes, such as energy metabolism, autophagy, and Sonic Hedgehog signaling, is also discussed. Finally, this review intends to stimulate future research directions to explore whether the impairment of astrocytic SREBP-2-mediated cholesterol synthesis in HD associates with other cellular dysfunctions in the disease.

Huntington's disease (HD) is a progressive neurodegenerative disorder, and increasing evidence suggests that inflammation, both central and peripheral, plays a role in disease progression. Neurohistology and neuroimaging studies illustrate neuroinflammatory processes as part of HD pathophysiology. Furthermore, studies of blood and cerebrospinal fluid from HD patients show altered levels of inflammatory markers and immune cell populations that could influence neuroinflammation and the neurodegenerative process. Here, we review findings contributing to our understanding of the significance of immune activation in HD pathology. We discuss evidence of intrinsic effects of mutant huntingtin within immune cells and central immune alterations that contribute to neuroinflammation and neurodegeneration. We address the roles of central immune cells, as well as the potential contributions of peripheral signals and cell types in HD immune activation. We further discuss opportunities and challenges in utilizing immune-modulation strategies for future treatment approaches. A better understanding of neuroimmune interactions in HD can provide insights for manipulating these responses, potentially facilitating the development of therapies aimed at reducing the impact of neuroinflammatory and degenerative processes.

The glymphatic system, a macroscopic waste clearance network in the brain, plays a vital role in maintaining neuronal health and brain homeostasis. Functionally analogous to the lymphatic system in other organs, the term "glymphatic" combines "glial" and "lymphatic." This system facilitates the exchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF) in the parenchyma, aiding in the removal of soluble proteins and metabolites while distributing essential nutrients and signaling molecules. Its functionality is closely tied to aquaporin 4 (AQP4) water channels, located primarily on astrocytic endfeet, which mediate water movement between the CSF and ISF. Proper glymphatic function relies on the cellular distribution of AQP4 channels and its astroglial endfeet polarization. Emerging evidence links glymphatic dysfunction to several neurodegenerative disorders, including Huntington's disease (HD). Understanding the role of the glymphatic system in HD pathogenesis could provide novel insights into disease pathogenesis and new therapeutic approaches. This review examines the connection between glymphatic dysfunction and HD, highlighting future research directions and therapeutic advancement for HD. It explores pharmacological interventions and lifestyle modifications aimed at optimizing glymphatic function to improve HD management.

BackgroundWork plays a crucial role in life, contributing to financial stability and well-being. Huntington's disease (HD), a genetic neurodegenerative disorder, can significantly affect work capacity. Anosognosia (lack of awareness of impairments) and avoidant coping are common in HD but remain unexplored in relation to work outcomes.ObjectiveThis study investigated the relationships between anosognosia, coping styles, and work capacity in individuals with pre-motor manifest and motor manifest HD.MethodsUtilizing the HD-Work dataset, we analyzed motor and cognitive functioning, coping styles, work capacity, and anosognosia in participants with pre-motor manifest and motor manifest HD (n = 117). Anosognosia was operationalized through expert rating, participant - proxy, and cognitive - performance discrepancies. Work capacity was measured using the occupation item of the Total Functional Capacity scale, and coping styles were assessed with the Utrechtse Coping Lijst.ResultsAnosognosia was strongly associated with cognitive decline, while avoidant coping was less prevalent. Both anosognosia and avoidance coping were correlated with frontal behaviors but not with work capacity. A positive association between avoidant coping and anosognosia was found. The most common coping style used was passive coping. Participants did not often seek social comfort.ConclusionsThe best predictor of anosognosia was cognitive decline. The positive association between avoidant coping and anosognosia suggested a potential misattribution of avoidant coping to anosognosia. This study emphasized the importance of recognizing avoidant and passive coping strategies in early-stage HD, as well as anosognosia in relation to cognitive decline, even though these factors do not directly impact work capacity.

BackgroundHuntington's disease is a progressive, autosomal dominant, neurodegenerative disease caused by a CAG repeat expansion in the HTT gene. Medium spiny neurons of the striatum are especially vulnerable to the disease, and atrophy of the caudate and putamen can be documented by neuroimaging years before the onset of symptoms.ObjectiveIn this study, we aimed to characterize region-specific gray and white matter differences between Huntington's disease patients and controls.MethodsWe conducted a postmortem MRI study of the brains of 15 adults diagnosed with symptomatic Huntington's disease and 26 control subjects, aiming to compare the differences in regional grey and white matter volumes between the two groups.ResultsThe study revealed decreased volumes in both grey and white matter in patients with Huntington's disease, with the largest effect sizes observed in caudate and putamen. Notably, the atrophy predominantly affected the left hemisphere, particularly impacting grey and white matter regions adjacent to the pars opercularis, precentral, supramarginal, and pars orbitalis gyri, and the lateral orbitofrontal cortex. In the control group, asymmetry stems from larger left hemisphere regions compared to right, whereas an opposite pattern is observed in the Huntington's disease group.ConclusionsThese results suggest progressive, diffuse, and asymmetric grey and white matter atrophy occurs in Huntington's disease. The reasons for this asymmetry remain unknown; however, our study provides a more detailed characterization of previously reported grey and white matter changes in Huntington's disease, as observed through postmortem histopathological and MRI studies.

BackgroundCurrent functional rating scales are not sensitive to the earliest functional changes in Huntington's disease (HD).ObjectiveThe Functional Rating Scale 2.0 (FuRST 2.0) is a patient-reported outcome (PRO) measure designed to be sensitive to the initial functional changes in HD, specifically stage 2 and mild stage 3, as defined by the Huntington's Disease Integrated Staging System (HD-ISS).MethodsWe followed standard assessment development methodology to create a PRO. Study 1 consisted of a Delphi panel which analyzed data from focus groups comprised of people with HD and companions from 6 countries. This was followed by four rounds of cognitive interviews through which we evaluated respondents' comprehension of the instructions, understanding of question and response options, and comfort with the material. Informal advice from a regulatory agency was garnered throughout the process.ResultsConcerns from the target population and regulators regarding instructions, questions, response options, and comfort with the material were addressed through modifications to the scale's wording and format.ConclusionsWe developed the FuRST 2.0 official working document (OWD), the penultimate version of the scale, using focus groups, a Delphi panel, iterative rounds of cognitive interviewing, and informal regulatory advice. Its psychometric properties are being evaluated in the FOCUS-HD validation studies from which the final version of the scale will be derived. The FuRST 2.0 OWD is available for use.

BackgroundDeutetrabenazine, a vesicular monoamine transporter 2 inhibitor, is one of few treatment options available for Huntington's disease (HD) chorea. There is limited data describing clinical experience with deutetrabenazine doses >48 mg daily.ObjectiveDescribe treatment outcomes for deutetrabenazine >48 mg daily.MethodsA dual site retrospective cohort study of patients on deutetrabenazine titrated to doses >48 mg/day for HD chorea from April 2017 through December 2021 was conducted. Patients using concomitant strong CYP2D6 inhibitors at time of deutetrabenazine initiation, those who became deceased or lost to follow-up within six months of dose increase above 48 mg/day, or previously enrolled in a study on >48 mg daily and moving to commercial product were excluded. Outcomes were reported descriptively including therapeutic response, adverse effects (AEs), adherence (measured by proportion of days covered [PDC]), and discontinuation.ResultsThirty patients were included: 47% female, 93% White, median age 56 years. Most patients required dose escalations for inadequate response. The rate of AEs reported before and after transitioning to doses >48 mg/day was the same. Psychiatric changes were less commonly reported at doses >48 mg/day, but extrapyramidal symptoms were more common. The median total maximum chorea score in the Unified HD Rating Scale was 13 (IQR 9-19) and 13 (IQR 7-18) at baseline and follow-up, respectively. Median PDC was 0.99 (IQR 0.94-1.00); two patients discontinued therapy due to AEs.ConclusionsDeutetrabenazine >48 mg daily appears safe and well tolerated in patients with uncontrolled HD chorea, though no significant change in total maximal chorea score was found.

BackgroundHuntington's disease (HD) leads to a decline in functional capacity, affecting daily life tasks. Assessing functional capacity in clinical trials is crucial to evaluate treatment effectiveness and substantiate the clinical meaningfulness of more sensitive and reliable measures. Clinician rating scales are commonly used, but performance-based measures of functional capacity may offer advantages, however, there is no consensus on the suitability of existing performance-based measures for use in HD.ObjectiveWe applied a Consensus-based Standards for the selection of health Measurement INstruments (COSMIN) approach to evaluate the potential suitability of performance-based functional capacity measures for HD clinical trials. We also used criteria developed with expert input to assess these measures.MethodsWe conducted a systematic search of relevant databases and screened 1924 articles for inclusion criteria.ResultsWe included a total of 89 articles on 33 performance-based functional capacity measures. Measures were rated from Very Low to Moderate suitability for use in HD clinical trials. DriveSafe DriveAware and EcoKitchen were the only measures tested in HD participants and were rated as having Moderate and Very Low suitability respectively, highlighting the need for further evaluation. Additionally, the Brief University of California San Diego Performance-based Skills Assessment (UCSD UPSA-B) and the Virtual Reality Functional Capacity Assessment Tool (VRFCAT), were identified as potentially useful, also rated Moderate.ConclusionsMultiple performance-based functional capacity measures show potential for use in patients with HD, pending further investigation.