Journal of Huntington's disease最新文献

{"title":"A Randomized Controlled Trial of Probiotics Targeting Gut Dysbiosis in Huntington's Disease.","authors":"Cory I Wasser,&nbsp;Emily-Clare Mercieca,&nbsp;Geraldine Kong,&nbsp;Anthony J Hannan,&nbsp;Brianna Allford,&nbsp;Sonja J McKeown,&nbsp;Julie C Stout,&nbsp;Yifat Glikmann-Johnston","doi":"10.3233/JHD-220556","DOIUrl":"https://doi.org/10.3233/JHD-220556","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":"12 1","pages":"43-55"},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9669930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preface to the Special Issue on \"Sleep and Circadian Disorder in Huntington's Disease\".","authors":"Blair R Leavitt,&nbsp;Leslie M Thompson","doi":"10.3233/JHD-239002","DOIUrl":"https://doi.org/10.3233/JHD-239002","url":null,"abstract":"","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":"12 2","pages":"89"},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/df/1b/jhd-12-jhd239002.PMC10473054.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10137358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Huntingtin Plays a Role in the Physiological Response to Ethanol in Drosophila.","authors":"Erin B D Clabough,&nbsp;Christia Aspili,&nbsp;William S Fussy,&nbsp;James D Ingersoll,&nbsp;Amy Kislyakov,&nbsp;Elizabeth S Li,&nbsp;Meng-Jiuan Su,&nbsp;Dustin B Wiles,&nbsp;Thomas E Watson,&nbsp;Aaron J Willy,&nbsp;H Thomas Vinyard,&nbsp;Philip J Mollica Iii,&nbsp;James V Taylor,&nbsp;Cody W Smith,&nbsp;Dallas A Roark,&nbsp;Zachary P Tabrani,&nbsp;Harris L Thomas,&nbsp;Mimi Shin,&nbsp;B Jill Venton,&nbsp;David Hayes,&nbsp;Conor W Sipe","doi":"10.3233/JHD-230581","DOIUrl":"10.3233/JHD-230581","url":null,"abstract":"<p><strong>Background: </strong>Huntingtin (htt) protein is an essential regulator of nervous system function through its various neuroprotective and pro-survival functions, and loss of wild-type htt function is implicated in the etiology of Huntington's disease. While its pathological role is typically understood as a toxic gain-of-function, some neuronal phenotypes also result from htt loss. Therefore, it is important to understand possible roles for htt in other physiological circumstances.</p><p><strong>Objective: </strong>To elucidate the role of htt in the context of ethanol exposure, we investigated how loss of htt impacts behavioral and physiological responses to ethanol in Drosophila.</p><p><strong>Methods: </strong>We tested flies lacking htt for ethanol sensitivity and tolerance, preference for ethanol using capillary feeder assays, and recovery of mobility after intoxication. Levels of dopamine neurotransmitter and numbers of dopaminergic cells in brains lacking dhtt were also measured.</p><p><strong>Results: </strong>We found that dhtt-null flies are both less sensitive and more tolerant to ethanol exposure in adulthood. Moreover, flies lacking dhtt are more averse to alcohol than controls, and they recover mobility faster following acute ethanol intoxication. We showed that dhtt mediates these effects at least in part through the dopaminergic system, as dhtt is required to maintain normal levels of dopamine in the brain and normal numbers of dopaminergic cells in the adult protocerebrum.</p><p><strong>Conclusions: </strong>Our results demonstrate that htt regulates the physiological response to ethanol and indicate a novel neuroprotective role for htt in the dopaminergic system, raising the possibility that it may be involved more generally in the response to toxic stimuli.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"241-252"},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10144006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Amendment of Altered Immune Response by Curcumin in Drosophila Model of Huntington's Disease.","authors":"Jyoti Dhankhar, Anju Shrivastava, Namita Agrawal","doi":"10.3233/JHD-230595","DOIUrl":"10.3233/JHD-230595","url":null,"abstract":"<p><strong>Background: </strong>Though primarily classified as a brain disorder, surplus studies direct Huntington's disease (HD) to be a multi-system disorder affecting various tissues and organs, thus affecting overall physiology of host. Recently, we have reported that neuronal expression of mutant huntingtin induces immune dysregulation in Drosophila and may pose chronic threat to challenged individuals. Therefore, we tested the polyphenolic compound curcumin to circumvent the impact of immune dysregulation in Drosophila model of HD.</p><p><strong>Objective: </strong>The present study examined the molecular basis underlying immune derangements and immunomodulatory potential of curcumin in HD.</p><p><strong>Methods: </strong>UAS-GAL4 system was used to imitate the HD symptoms in Drosophila, and the desired female progenies (elav > Httex1pQ25; control and elav > Httex1pQ93; diseased) were cultured on food mixed without and with 10 μM concentration of curcumin since early development. Effect of curcumin supplementation was investigated by monitoring the hemocytes' count and their functional abilities in diseased condition. Reactive oxygen species (ROS) level in cells was assessed by DHE staining and mitochondrial dysfunction was assessed by CMXros red dye. In addition, transcript levels of pro-inflammatory cytokines and anti-microbial peptides were monitored by qRT-PCR.</p><p><strong>Results: </strong>We found that curcumin supplementation commendably reduced higher crystal cell count and phenoloxidase activity in diseased flies. Interestingly, curcumin significantly managed altered plasmatocytes count, improved their phagocytic activity by upregulating the expression of key phagocytic receptors in HD condition. Moreover, substantial alleviation of ROS levels and mitochondria dysfunction was observed in plasmatocytes of diseased flies upon curcumin supplementation. Furthermore, curcumin administration effectively attenuated transcriptional expression of pro-inflammatory cytokines and AMPs in diseased flies.</p><p><strong>Conclusions: </strong>Our results indicate that curcumin efficiently attenuates immune derangements in HD flies and may prove beneficial in alleviating complexities associated with HD.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"335-354"},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41133953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"To Sleep to Dream … No More? The Quest for Restorative Sleep in Huntington's Disease, a Clinician's Perspective.","authors":"Herminia Diana Rosas","doi":"10.3233/JHD-230573","DOIUrl":"https://doi.org/10.3233/JHD-230573","url":null,"abstract":"<p><p>Sleep disorders are common in Huntington's disease (HD) but are complex; their bi-directional associations with psychiatric, cognitive, and motor dysfunction makes them especially important to both consider and to treat. The author provides a perspective in brief regarding sleep disturbances in HD, based on her experience caring for, and learning from, patients with HD for more than twenty years.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":"12 2","pages":"163-165"},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/11/a5/jhd-12-jhd230573.PMC10473094.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10493466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Untangling the Role of Tau in Huntington's Disease Pathology.","authors":"Shireen Salem,&nbsp;Francesca Cicchetti","doi":"10.3233/JHD-220557","DOIUrl":"https://doi.org/10.3233/JHD-220557","url":null,"abstract":"<p><p>There is increasing evidence for the presence of pathological forms of tau in tissues of both Huntington's disease (HD) patients and animal models of this condition. While cumulative studies of the past decade have led to the proposition that this disorder could also be considered a tauopathy, the implications of tau in cellular toxicity and consequent behavioral impairments are largely unknown. In fact, recent animal work has challenged the contributory role of tau in HD pathogenesis/pathophysiology. This review presents the supporting and opposing arguments for the involvement of tau in HD, highlighting the discrepancies that have emerged. Reflecting on what is known in other tauopathies, the putative mechanisms through which tau could initiate and/or contribute to pathology are discussed, shedding light on the future research directions that could be considered to confirm, or rule out, the clinical relevance of tau in HD.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":"12 1","pages":"15-29"},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/cf/b1/jhd-12-jhd220557.PMC10200181.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9663625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advance Care Planning in Huntington's Disease.","authors":"Mena Farag,&nbsp;Desiree M Salanio,&nbsp;Cara Hearst,&nbsp;Daniela Rae,&nbsp;Sarah J Tabrizi","doi":"10.3233/JHD-220559","DOIUrl":"https://doi.org/10.3233/JHD-220559","url":null,"abstract":"<p><p>Advance care planning (ACP) is a useful tool that benefits adult patients, care providers, and surrogate decision makers, through providing opportunities for patients to consider, express, and formalize their beliefs, preferences, and wishes pertaining to decisions regarding future medical care at a time when they retain decision-making capacity. Early and timely consideration of ACP discussions is paramount in Huntington's disease (HD) given the potential challenges in ascertaining decision-making capacity in the advanced stages of the disease. ACP helps to empower and extend patient autonomy, providing clinicians and surrogate decision makers with reassurance that management is consistent with a patient's expressed wishes. Regular follow up is vital to establish consistency of decisions and wishes. We outline the framework of the dedicated ACP clinic integrated within our HD service to highlight the importance of a patient-centred and tailored care plan that fulfils the patient's expressed goals, preferences, and values.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":"12 1","pages":"77-82"},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9719992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Applying the Huntington's Disease Integrated Staging System (HD-ISS) to Observational Studies.","authors":"Jeffrey D Long,&nbsp;Emily C Gantman,&nbsp;James A Mills,&nbsp;Jatin G Vaidya,&nbsp;Alexandra Mansbach,&nbsp;Sarah J Tabrizi,&nbsp;Cristina Sampaio","doi":"10.3233/JHD-220555","DOIUrl":"https://doi.org/10.3233/JHD-220555","url":null,"abstract":"<p><strong>Background: </strong>The Huntington's Disease Integrated Staging System (HD-ISS) has four stages that characterize disease progression. Classification is based on CAG length as a marker of Huntington's disease (Stage 0), striatum atrophy as a biomarker of pathogenesis (Stage 1), motor or cognitive deficits as HD signs and symptoms (Stage 2), and functional decline (Stage 3). One issue for implementation is the possibility that not all variables are measured in every study, and another issue is that the stages are broad and may benefit from progression subgrouping.</p><p><strong>Objective: </strong>Impute stages of the HD-ISS for observational studies in which missing data precludes direct stage classification, and then define progression subgroups within stages.</p><p><strong>Methods: </strong>A machine learning algorithm was used to impute stages. Agreement of the imputed stages with the observed stages was evaluated using graphical methods and propensity score matching. Subgroups were defined based on descriptive statistics and optimal cut-point analysis.</p><p><strong>Results: </strong>There was good overall agreement between the observed stages and the imputed stages, but the algorithm tended to over-assign Stage 0 and under-assign Stage 1 for individuals who were early in progression.</p><p><strong>Conclusion: </strong>There is evidence that the imputed stages can be treated similarly to the observed stages for large-scale analyses. When imaging data are not available, imputation can be avoided by collapsing the first two stages using the categories of Stage≤1, Stage 2, and Stage 3. Progression subgroups defined within a stage can help to identify groups of more homogeneous individuals.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":"12 1","pages":"57-69"},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9720497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Mammalian Circadian Time-Keeping System.","authors":"Andrew P Patton,&nbsp;Michael H Hastings","doi":"10.3233/JHD-230571","DOIUrl":"https://doi.org/10.3233/JHD-230571","url":null,"abstract":"<p><p>Our physiology and behavior follow precise daily programs that adapt us to the alternating opportunities and challenges of day and night. Under experimental isolation, these rhythms persist with a period of approximately one day (circadian), demonstrating their control by an internal autonomous clock. Circadian time is created at the cellular level by a transcriptional/translational feedback loop (TTFL) in which the protein products of the Period and Cryptochrome genes inhibit their own transcription. Because the accumulation of protein is slow and delayed, the system oscillates spontaneously with a period of ∼24 hours. This cell-autonomous TTFL controls cycles of gene expression in all major tissues and these cycles underpin our daily metabolic programs. In turn, our innumerable cellular clocks are coordinated by a central pacemaker, the suprachiasmatic nucleus (SCN) of the hypothalamus. When isolated in slice culture, the SCN TTFL and its dependent cycles of neural activity persist indefinitely, operating as \"a clock in a dish\". In vivo, SCN time is synchronized to solar time by direct innervation from specialized retinal photoreceptors. In turn, the precise circadian cycle of action potential firing signals SCN-generated time to hypothalamic and brain stem targets, which co-ordinate downstream autonomic, endocrine, and behavioral (feeding) cues to synchronize and sustain the distributed cellular clock network. Circadian time therefore pervades every level of biological organization, from molecules to society. Understanding its mechanisms offers important opportunities to mitigate the consequences of circadian disruption, so prevalent in modern societies, that arise from shiftwork, aging, and neurodegenerative diseases, not least Huntington's disease.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":"12 2","pages":"91-104"},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/b5/d7/jhd-12-jhd230571.PMC7614869.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10141666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Levels of Synaptic Proteins in Brain and Neurofilament Light Chain in Cerebrospinal Fluid and Plasma of OVT73 Huntington's Disease Sheep Support a Prodromal Disease State.","authors":"Ellen Sapp,&nbsp;Adel Boudi,&nbsp;Suzanne J Reid,&nbsp;Bianca A Trombetta,&nbsp;Pia Kivisäkk,&nbsp;Toloo Taghian,&nbsp;Steven E Arnold,&nbsp;David Howland,&nbsp;Heather Gray-Edwards,&nbsp;Kimberly B Kegel-Gleason,&nbsp;Marian DiFiglia","doi":"10.3233/JHD-230590","DOIUrl":"10.3233/JHD-230590","url":null,"abstract":"<p><strong>Background: </strong>Synaptic changes occur early in patients with Huntington's disease (HD) and in mouse models of HD. An analysis of synaptic changes in HD transgenic sheep (OVT73) is fitting since they have been shown to have some phenotypes. They also have larger brains, longer lifespan, and greater motor and cognitive capacities more aligned with humans, and can provide abundant biofluids for in vivo monitoring of therapeutic interventions.</p><p><strong>Objective: </strong>The objective of this study was to determine if there were differences between 5- and 10-year-old OVT73 and wild-type (WT) sheep in levels of synaptic proteins in brain and in neurofilament light chain (NfL) in cerebrospinal fluid (CSF) and plasma.</p><p><strong>Methods: </strong>Mutant huntingtin (mHTT) and other proteins were measured by western blot assay in synaptosomes prepared from caudate, motor, and piriform cortex in 5-year-old and caudate, putamen, motor; and piriform cortex in 10-year-old WT and OVT73 sheep. Levels of NfL, a biomarker for neuronal damage increased in many neurological disorders including HD, were examined in CSF and plasma samples from 10-year-old WT and OVT73 sheep using the Simoa NfL Advantage kit.</p><p><strong>Results: </strong>Western blot analysis showed mHTT protein expression in synaptosomes from OVT73 sheep was  23% of endogenous sheep HTT levels at both ages. Significant changes were detected in brain levels of PDE10A, SCN4B, DARPP32, calmodulin, SNAP25, PSD95, VGLUT 1, VAMP1, and Na+/K+-ATPase, which depended on age and brain region. There was no difference in NfL levels in CSF and plasma in OVT73 sheep compared to age-matched WT sheep.</p><p><strong>Conclusions: </strong>These results show that synaptic changes occur in brain of 5- and 10-year-old OVT73 sheep, but levels of NfL in biofluids are unaffected. Altogether, the data support a prodromal disease state in OVT73 sheep that involves the caudate, putamen and cortex.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"201-213"},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10149427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}