Journal of Huntington's disease最新文献

{"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}

{"title":"Pharmacological Co-Activation of TrkB and TrkC Receptor Signaling Ameliorates Striatal Neuropathology and Motor Deficits in Mouse Models of Huntington's Disease.","authors":"Danielle A Simmons,&nbsp;Nadia P Belichenko,&nbsp;Frank M Longo","doi":"10.3233/JHD-230589","DOIUrl":"10.3233/JHD-230589","url":null,"abstract":"<p><strong>Background: </strong>Loss of neurotrophic support in the striatum, particularly reduced brain-derived neurotrophic factor (BDNF) levels, contributes importantly to Huntington's disease (HD) pathogenesis. Another neurotrophin (NT), NT-3, is reduced in the cortex of HD patients; however, its role in HD is unknown. BDNF and NT-3 bind with high affinity to the tropomyosin receptor-kinases (Trk) B and TrkC, respectively. Targeting TrkB/TrkC may be an effective HD therapeutic strategy, as multiple links exist between their signaling pathways and HD degenerative mechanisms. We developed a small molecule ligand, LM22B-10, that activates TrkB and TrkC to promote cell survival.</p><p><strong>Objective: </strong>This study aimed to determine if upregulating TrkB/TrkC signaling with LM22B-10 would alleviate the HD phenotype in R6/2 and Q140 mice.</p><p><strong>Methods: </strong>LM22B-10 was delivered by concomitant intranasal-intraperitoneal routes to R6/2 and Q140 mice and then motor performance and striatal pathology were evaluated.</p><p><strong>Results: </strong>NT-3 levels, TrkB/TrkC phosphorylation, and AKT signaling were reduced in the R6/2 striatum; LM22B-10 counteracted these deficits. LM22B-10 also reduced intranuclear huntingtin aggregates, dendritic spine loss, microglial activation, and degeneration of dopamine- and cyclic AMP-regulated phosphoprotein with a molecular weight of 32 kDa (DARPP-32) and parvalbumin-containing neurons in the R6/2 and/or Q140 striatum. Moreover, both HD mouse models showed improved motor performance after LM22B-10 treatment.</p><p><strong>Conclusions: </strong>These results reveal an NT-3/TrkC signaling deficiency in the striatum of R6/2 mice, support the idea that targeting TrkB/TrkC alleviates HD-related neurodegeneration and motor dysfunction, and suggest a novel, disease-modifying, multi-target strategy for treating HD.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"215-239"},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10085882","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":"Dysregulation of Human Juvenile Huntington's Disease Brain Proteomes in Cortex and Putamen Involves Mitochondrial and Neuropeptide Systems.","authors":"Sonia Podvin, Charles Mosier, William Poon, Enlin Wei, Leigh-Ana Rossitto, Vivian Hook","doi":"10.3233/JHD-230577","DOIUrl":"10.3233/JHD-230577","url":null,"abstract":"<p><strong>Background: </strong>Huntington's disease (HD) is a genetic neurodegenerative disease caused by trinucleotide repeat CAG expansions in the human HTT gene. Early onset juvenile HD (JHD) in children is the most severe form of the disease caused by high CAG repeat numbers of the HTT gene.</p><p><strong>Objective: </strong>To gain understanding of human HD mechanisms hypothesized to involve dysregulated proteomes of brain regions that regulate motor and cognitive functions, this study analyzed the proteomes of human JHD cortex and putamen brain regions compared to age-matched controls.</p><p><strong>Methods: </strong>JHD and age-matched control brain tissues were assessed for CAG repeat numbers of HTT by PCR. Human brain JHD brain cortex regions of BA4 and BA6 with the putamen region (n = 5) were analyzed by global proteomics, compared to age-matched controls (n = 7). Protein interaction pathways were assessed by gene ontology (GO), STRING-db, and KEGG bioinformatics.</p><p><strong>Results: </strong>JHD brain tissues were heterozygous for one mutant HTT allele containing 60 to 120 CAG repeats, and one normal HTT allele with 10 to 19 CAG repeats. Proteomics data for JHD brain regions showed dysregulated mitochondrial energy pathways and changes in synaptic systems including peptide neurotransmitters. JHD compared to control proteomes of cortex and putamen displayed (a) proteins present only in JHD, (b) proteins absent in JHD, and (c) proteins that were downregulated or upregulated.</p><p><strong>Conclusions: </strong>Human JHD brain cortex and putamen regions display significant dysregulation of proteomes representing deficits in mitochondrial and synaptic neurotransmission functions. These findings advance understanding of JHD brain molecular mechanisms associated with HD disabilities.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":"12 4","pages":"315-333"},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138805858","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":"Altered Adipocyte Cell Size Distribution Prior to Weight Loss in the R6/2 Model of Huntington's Disease.","authors":"Elna Dickson,&nbsp;Claes Fryklund,&nbsp;Rana Soylu-Kucharz,&nbsp;Marie Sjögren,&nbsp;Karin G Stenkula,&nbsp;Maria Björkqvist","doi":"10.3233/JHD-230587","DOIUrl":"10.3233/JHD-230587","url":null,"abstract":"<p><strong>Background: </strong>Metabolic alterations contribute to disease onset and prognosis of Huntington's disease (HD). Weight loss in the R6/2 mouse model of HD is a consistent feature, with onset in mid-to-late stage of disease.</p><p><strong>Objective: </strong>In the present study, we aimed to investigate molecular and functional changes in white adipose tissue (WAT) that occur at weight loss in R6/2 mice. We further elaborated on the effect of leptin-deficiency and early obesity in R6/2 mice.</p><p><strong>Methods: </strong>We performed analyses at 12 weeks of age; a time point that coincides with the start of weight loss in our R6/2 mouse colony. Gonadal (visceral) and inguinal (subcutaneous) WAT depot weights were monitored, as well as adipocyte size distribution. Response to isoprenaline-stimulated glycerol release and insulin-stimulated glucose uptake in adipocytes from gonadal WAT was assessed.</p><p><strong>Results: </strong>In R6/2 mice, WAT depot weights were comparable to wildtype (WT) mice, and the response to insulin and isoprenaline in gonadal adipocytes was unaltered. Leptin-deficient R6/2 mice exhibited distinct changes compared to leptin-deficient WT mice. At 12 weeks, female leptin-deficient R6/2 mice had reduced body weight accompanied by an increased proportion of smaller adipocytes, while in contrast; male mice displayed a shift towards larger adipocyte sizes without a significant body weight reduction at this timepoint.</p><p><strong>Conclusions: </strong>We here show that there are early sex-specific changes in adipocyte cell size distribution in WAT of R6/2 mice and leptin-deficient R6/2 mice.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"253-266"},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10634637","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":"Upcoming Meetings Related to Huntington's Disease.","authors":"","doi":"10.3233/JHD-239006","DOIUrl":"https://doi.org/10.3233/JHD-239006","url":null,"abstract":"","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":"12 3","pages":"313"},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41135634","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":"Sleep Dysfunction in Huntington's Disease: Impacts of Current Medications and Prospects for Treatment.","authors":"Natalia E Owen, Roger A Barker, Zanna J Voysey","doi":"10.3233/JHD-230567","DOIUrl":"10.3233/JHD-230567","url":null,"abstract":"<p><p>Sleep dysfunction is highly prevalent in Huntington's disease (HD). Increasing evidence suggests that such dysfunction not only impairs quality of life and exacerbates symptoms but may even accelerate the underlying disease process. Despite this, current HD treatment approaches neither consider the impact of commonly used medications on sleep, nor directly tackle sleep dysfunction. In this review, we discuss approaches to these two areas, evaluating not only literature from clinical studies in HD, but also that from parallel neurodegenerative conditions and preclinical models of HD. We conclude by summarizing a hierarchical framework of current medications with regard to their impact on sleep, and by outlining key emerging sleep therapies.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":"12 2","pages":"149-161"},"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/5d/6e/jhd-12-jhd230567.PMC10473096.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10133003","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":"Sleep Disorders and Circadian Disruption in Huntington's Disease.","authors":"Sandra Saade-Lemus,&nbsp;Aleksandar Videnovic","doi":"10.3233/JHD-230576","DOIUrl":"https://doi.org/10.3233/JHD-230576","url":null,"abstract":"<p><p>Sleep and circadian alterations are common in patients with Huntington's disease (HD). Understanding the pathophysiology of these alterations and their association with disease progression and morbidity can guide HD management. We provide a narrative review of the clinical and basic-science studies centered on sleep and circadian function on HD. Sleep/wake disturbances among HD patients share many similarities with other neurodegenerative diseases. Overall, HD patients and animal models of the disease present with sleep changes early in the clinical course of the disease, including difficulties with sleep initiation and maintenance leading to decreased sleep efficiency, and progressive deterioration of normal sleep architecture. Despite this, sleep alterations remain frequently under-reported by patients and under-recognized by health professionals. The degree of sleep and circadian alterations has not consistently shown to be CAG dose-dependent. Evidence based treatment recommendations are insufficient due to lack of well-designed intervention trials. Approaches aimed at improving circadian entrainment, such as including light therapy, and time-restricted feeding have demonstrated a potential to delay symptom progression in some basic HD investigations. Larger study cohorts, comprehensive assessment of sleep and circadian function, and reproducibility of findings are needed in future in order to better understand sleep and circadian function in HD and to develop effective treatments.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":"12 2","pages":"121-131"},"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/b2/11/jhd-12-jhd230576.PMC10473087.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10142769","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}