Journal of Huntington's disease最新文献_第9页

Pharmacological Co-Activation of TrkB and TrkC Receptor Signaling Ameliorates Striatal Neuropathology and Motor Deficits in Mouse Models of Huntington's Disease. TrkB和TrkC受体信号传导的药理学共激活改善亨廷顿舞蹈症小鼠模型的纹状体神经病理和运动缺陷。

IF 3.1

Journal of Huntington's disease Pub Date : 2023-01-01 DOI: 10.3233/JHD-230589

Danielle A Simmons, Nadia P Belichenko, Frank M Longo

{"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, Nadia P Belichenko, Frank M Longo","doi":"10.3233/JHD-230589","DOIUrl":"10.3233/JHD-230589","url":null,"abstract":"Background: 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.Objective: This study aimed to determine if upregulating TrkB/TrkC signaling with LM22B-10 would alleviate the HD phenotype in R6/2 and Q140 mice.Methods: LM22B-10 was delivered by concomitant intranasal-intraperitoneal routes to R6/2 and Q140 mice and then motor performance and striatal pathology were evaluated.Results: 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.Conclusions: 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.","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}

引用次数: 0

Dysregulation of Human Juvenile Huntington's Disease Brain Proteomes in Cortex and Putamen Involves Mitochondrial and Neuropeptide Systems. 人类幼年亨廷顿氏病大脑皮层和普塔门蛋白质组的失调涉及线粒体和神经肽系统

IF 3.1

Journal of Huntington's disease Pub Date : 2023-01-01 DOI: 10.3233/JHD-230577

Sonia Podvin, Charles Mosier, William Poon, Enlin Wei, Leigh-Ana Rossitto, Vivian Hook

{"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":"Background: 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.Objective: 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.Methods: 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.Results: 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.Conclusions: 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.","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}

引用次数: 0

Altered Adipocyte Cell Size Distribution Prior to Weight Loss in the R6/2 Model of Huntington's Disease. 亨廷顿舞蹈症R6/2模型减肥前脂肪细胞大小分布的改变。

IF 3.1

Journal of Huntington's disease Pub Date : 2023-01-01 DOI: 10.3233/JHD-230587

Elna Dickson, Claes Fryklund, Rana Soylu-Kucharz, Marie Sjögren, Karin G Stenkula, Maria Björkqvist

{"title":"Altered Adipocyte Cell Size Distribution Prior to Weight Loss in the R6/2 Model of Huntington's Disease.","authors":"Elna Dickson, Claes Fryklund, Rana Soylu-Kucharz, Marie Sjögren, Karin G Stenkula, Maria Björkqvist","doi":"10.3233/JHD-230587","DOIUrl":"10.3233/JHD-230587","url":null,"abstract":"Background: 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.Objective: 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.Methods: 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.Results: 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.Conclusions: 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.","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}

引用次数: 0

Upcoming Meetings Related to Huntington's Disease. 即将召开的亨廷顿舞蹈症相关会议。

IF 3.1

Journal of Huntington's disease Pub Date : 2023-01-01 DOI: 10.3233/JHD-239006

引用次数: 0

Sleep Dysfunction in Huntington's Disease: Impacts of Current Medications and Prospects for Treatment. 亨廷顿舞蹈症的睡眠功能障碍：当前药物的影响和治疗前景》。

IF 3.1

Journal of Huntington's disease Pub Date : 2023-01-01 DOI: 10.3233/JHD-230567

Natalia E Owen, Roger A Barker, Zanna J Voysey

引用次数: 0

Sleep Disorders and Circadian Disruption in Huntington's Disease. 亨廷顿舞蹈病的睡眠障碍和昼夜节律紊乱。

IF 3.1

Journal of Huntington's disease Pub Date : 2023-01-01 DOI: 10.3233/JHD-230576

Sandra Saade-Lemus, Aleksandar Videnovic

{"title":"Sleep Disorders and Circadian Disruption in Huntington's Disease.","authors":"Sandra Saade-Lemus, Aleksandar Videnovic","doi":"10.3233/JHD-230576","DOIUrl":"https://doi.org/10.3233/JHD-230576","url":null,"abstract":"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.","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}

引用次数: 1

Intrapersonal and Interpersonal Disengagement Coping: Associations with Emotions of Youth At-Risk for Huntington's Disease. 个人内部和人际脱离应对：与亨廷顿舞蹈症高危青年情绪的关系。

IF 3.1

Journal of Huntington's disease Pub Date : 2023-01-01 DOI: 10.3233/JHD-230566

Kelly H Watson, Abagail E Ciriegio, Anna C Pfalzer, Abigail Snow, Lisa Hale, Spencer Diehl, Katherine E McDonell, Daniel O Claassen, Bruce E Compas

{"title":"Intrapersonal and Interpersonal Disengagement Coping: Associations with Emotions of Youth At-Risk for Huntington's Disease.","authors":"Kelly H Watson, Abagail E Ciriegio, Anna C Pfalzer, Abigail Snow, Lisa Hale, Spencer Diehl, Katherine E McDonell, Daniel O Claassen, Bruce E Compas","doi":"10.3233/JHD-230566","DOIUrl":"10.3233/JHD-230566","url":null,"abstract":"Background: Families in which a parent has Huntington's disease (HD) are faced with significant stressors that can contribute to difficulties in communicating together about illness-related concerns. Family members who use more disengagement coping strategies, including denial and avoidance, to deal with illness-related stressors may have the greatest challenges to effective communication.Objective: The current study examined the associations of intrapersonal and interpersonal disengagement coping responses with observed and reported emotions of adolescents and young adults (AYA) at genetic risk for HD.Methods: Families included 42 AYA (n = 26 females) ages 10 to 34 (M = 19 years, 11 months; SD = 7 years, 6 months) and their parent with HD (n = 22 females, M age = 46 years, 10 months; SD = 9 years, 2 months). Dyads participated in observations of communication and completed questionnaires about disengagement coping and internalizing symptoms.Results: Disengagement coping of AYA was unrelated to their observed and reported emotional difficulties (intrapersonal coping). However, there was evidence for the importance of interpersonal disengagement coping, as AYA's negative affect was observed and reported to be highest when both AYA and their parents reported using high levels of avoidance, denial, and wishful thinking to cope with HD-related stress.Conclusion: The findings underscore the importance of a family-oriented approach to coping and communication in families affected by HD.","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"305-312"},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9711656","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}

引用次数: 0

Frailty and Associated Environmental Factors Only Have Small Effects on Age of Onset in Huntington's Disease. 虚弱和相关环境因素对亨廷顿氏病发病年龄的影响很小。

IF 3.1

Journal of Huntington's disease Pub Date : 2023-01-01 DOI: 10.3233/JHD-230572

Niroshan Jeyakumar, Sarah N Hilmer, Armando Teixeira-Pinto, Clement T Loy

{"title":"Frailty and Associated Environmental Factors Only Have Small Effects on Age of Onset in Huntington's Disease.","authors":"Niroshan Jeyakumar, Sarah N Hilmer, Armando Teixeira-Pinto, Clement T Loy","doi":"10.3233/JHD-230572","DOIUrl":"10.3233/JHD-230572","url":null,"abstract":"Background: Over one third of age of onset variation in Huntington's disease is unexplained by CAG repeat length. In Alzheimer's disease, frailty partly modulates the relationship between neuropathology and dementia.Objective: We investigated whether a multi-domain frailty index, reflecting non-genetic factors in Huntington's disease, similarly modulates the relationship between CAG repeat length and age of onset.Methods: We created a frailty index assessing comorbidities, substance abuse, polypharmacy, and education. We applied multiple linear regression models to 2,741 subjects with manifest Huntington's disease from the Enroll-HD cohort study, including 729 subjects with late-onset (post-60 years) disease, using frailty index or constituent item scores and CAG repeat length as independent variables. We used actual and \"residual\" ages of onset (difference between actual and CAG-based predicted onset) as dependent variables, the latter offsetting the increased time available to accumulate comorbidities in older subjects.Results: Higher frailty index scores were associated with significantly lower residual ages of onset in the late-onset subgroup (p = 0.03), though the effect was small (R2 = 0.27 with frailty as a predictor vs. 0.26 without). Number of comorbidities was also associated with significantly lower residual ages of onset in the late-onset subgroup (p = 0.04). Drug abuse and smoking were associated with significantly earlier ages of onset in the whole cohort (p < 0.01, p = 0.02) and late-onset subgroup (p < 0.01, p = 0.03).Conclusions: The impact of non-genetic factors on age of onset, assessed using a frailty index or separately, in Huntington's disease is limited.","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"355-361"},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138440811","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}

引用次数: 0

Huntington's and the History of Sleep. 亨廷顿舞蹈症和睡眠的历史。

IF 3.1

Journal of Huntington's disease Pub Date : 2023-01-01 DOI: 10.3233/JHD-230568

Alice R Wexler

{"title":"Huntington's and the History of Sleep.","authors":"Alice R Wexler","doi":"10.3233/JHD-230568","DOIUrl":"https://doi.org/10.3233/JHD-230568","url":null,"abstract":"Long before I first heard the words Huntington’s disease, I had trouble sleeping: difficulty falling asleep, problems staying asleep. Even as a kid I worried about sleep. My therapist father would comfort me, telling me not to worry; resting in bed, he would say, was almost like sleeping: not the advice sleep experts give today. He too had trouble sleeping. My sister Nancy, on the other hand, has been a gifted sleeper most her life. From the time she was little, she could fall asleep instantly at night, in the car on road trips, and on planes during long flights. Mostly she stayed awake and alert during the day. Her sleep changed as Huntington’s symptoms emerged, long before her diagnosis. She began falling asleep during the day, dozing off at meetings or in front of her computer. I attributed her daytime sleepiness to her overbooked schedule and lack of time in bed due to heavy professional and social commitments. With her diagnosis—followed several months later by the pandemic—she began staying up extremely late; she awoke more often during the night and had more difficulty returning to sleep; she slept late, sometimes past noon, though once awake, she usually remained so. No matter if her partner without Huntington’s followed a regular timetable, going to bed and awakening at more or less his typical workday hour, Nancy’s pattern did not adapt. Even as her Huntington’s progresses, my sister remains a free spirit. With few externally-imposed commitments, she can follow her circadian rhythms wherever they take her, though not without pressures from others in the household to follow a more conventional","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":"12 2","pages":"167-168"},"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/bf/58/jhd-12-jhd230568.PMC10473129.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10512059","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}

引用次数: 0

Supporting Huntington's Disease Families Through the Ups and Downs of Clinical Trials. 通过临床试验的起起伏伏来支持亨廷顿舞蹈症家庭。

IF 3.1

Journal of Huntington's disease Pub Date : 2023-01-01 DOI: 10.3233/JHD-230565

Kelly M Andrew, Leora M Fox

{"title":"Supporting Huntington's Disease Families Through the Ups and Downs of Clinical Trials.","authors":"Kelly M Andrew, Leora M Fox","doi":"10.3233/JHD-230565","DOIUrl":"https://doi.org/10.3233/JHD-230565","url":null,"abstract":"Recent years have been turbulent ones for the Huntington's disease (HD) community. Three clinical trials for HD, including the first Phase 3 trial of a potentially disease modifying genetic therapy for HD, were all brought to a halt in March of 2021. 2022 brought more study roadblocks and an additional trial termination. As HD science progresses and larger scale trials become more frequent in the community, HD families are faced with the difficult reality that clinical research rarely results in a new drug hitting the market. To better understand how the HD community can be prepared for the ups and downs that accompany an expanding clinical research pipeline, the Huntington's Disease Society of America (HDSA) spoke with members of the Huntington's Disease Coalition for Patient Engagement (HD-COPE). This group of global advocates led by HDSA and the Huntington's Society of Canada (HSC) collaborates with pharmaceutical companies to ensure that HD voices are represented in the planning of clinical trials. These conversations allowed HDSA to summarize how the HD community can be best supported through the clinical research process in three key areas: engagement, support, and education.","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":"12 1","pages":"71-76"},"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/0e/ae/jhd-12-jhd230565.PMC10200140.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10022276","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}

引用次数: 0