Pub Date : 2024-08-02DOI: 10.1101/2024.07.31.24311309
Zanna J Voysey, Anna OG Goodman, Lorraine Rogers, Jonathan A Holbrook, Alpar S Lazar, Roger A Barker
Increasing evidence suggests that the sleep pathology associated with neurodegenerative diseases can in turn exacerbate both the cognitive deficits and underlying pathobiology of these conditions. Treating sleep may therefore bear significant, even disease-modifying, potential for these conditions, but how best and when to do so remains undetermined. Huntingtons Disease (HD), by virtue of being an autosomal-dominant neurodegenerative disease presenting in mid-life, presents a key model condition through which to advance this field. To date, however, there has been no clinical longitudinal study of sleep abnormalities in HD, and no robust interrogation of their association with disease onset, cognitive deficits and markers of disease activity. Here we present the first such study. HD gene carriers (n=28) and age- and sex-matched controls (n=21) were studied at baseline and 10- and 12-year follow up. All HD gene carriers were premanifest at baseline, and were stratified at follow up into prodromal/manifest and premanifest groups. Sleep abnormalities were assessed through two-night inpatient polysomnography (PSG) and two-week domiciliary actigraphy, and their association was explored against i)validated cognitive and affective outcomes (Montreal Cognitive Assessment, Trail A/B task, Symbol Digit Modalities Task [SDMT], Hopkins Verbal Learning Task [HVLT], Montgomery-Asberg Depression Rating Scale [MADRS]) and ii)serum neurofilament-light (NfL) levels. Statistical analysis incorporated cross-sectional ANCOVA, longitudinal repeated measures linear models and regressions adjusted for multiple confounders including disease stage. 15 HD gene carriers phenoconverted to prodromal/early manifest HD by study completion. At follow-up, these gene carriers showed more frequent sleep stage changes (p=<0.001,partial eta squared=0.62) and higher levels of sleep maintenance insomnia (p=0.002,partial eta squared=0.52). The latter finding was corroborated by nocturnal motor activity patterns on follow-up actigraphy (p=0.004,partial eta squared=0.32). Greater sleep maintenance insomnia was associated with greater cognitive deficits (Trail A p=<0.001,R squared=0.78;SDMT p=0.008,R squared=0.63;Trail B p=0.013,R squared=0.60) and higher levels of NfL (p=0.015,R squared=0.39). Longitudinal modelling suggested that sleep stage instability accrues from the early premanifest phase, whereas sleep maintenance insomnia emerges closer to phenoconversion. Baseline sleep stage instability was able to discriminate those who phenoconverted within the study period from those who remained premanifest (area under curve=0.81,p=0.024). These results demonstrate that the key sleep abnormalities of premanifest/early HD are sleep stage instability and sleep maintenance insomnia, and suggest that the former bears value in predicting disease onset, while the latter is associated with greater disease activity and cognitive deficits. Intervention studies to interrogate causation within th
越来越多的证据表明，与神经退行性疾病相关的睡眠病理学反过来又会加剧这些疾病的认知缺陷和潜在病理生物学。因此，治疗睡眠可能会对这些疾病产生重大影响，甚至改变病情，但如何最好地治疗以及何时治疗仍未确定。亨廷顿斯病（Huntingtons Disease，HD）是一种常染色体显性遗传的神经退行性疾病，多发于中年时期，是推动这一领域发展的关键模型条件。然而，迄今为止，还没有对 HD 患者的睡眠异常进行过临床纵向研究，也没有对睡眠异常与疾病发病、认知障碍和疾病活动性标志物之间的关系进行过深入探讨。在此，我们介绍第一项此类研究。我们对 HD 基因携带者（28 人）以及年龄和性别匹配的对照组（21 人）进行了基线研究以及 10 年和 12 年的随访研究。所有 HD 基因携带者在基线时都是发病前状态，在随访时被分为前驱/发病组和发病前组。睡眠异常通过两晚住院多导睡眠图（PSG）和两周居家动态睡眠图进行评估，并探讨了睡眠异常与 i) 有效认知和情感结果（蒙特利尔认知评估、追踪 A/B 任务、符号数字模式任务 [SDMT]、霍普金斯言语学习任务 [HVLT]、蒙哥马利-阿斯伯格抑郁量表 [MADRS]）和 ii) 血清神经丝光 (NfL) 水平之间的关联。统计分析包括横断面方差分析、纵向重复测量线性模型以及根据疾病分期等多种混杂因素进行调整的回归分析。研究结束时，15 名 HD 基因携带者表观转化为前驱型/早期表现型 HD。在随访中，这些基因携带者表现出更频繁的睡眠阶段变化（p=<0.001,部分等方差=0.62）和更高程度的睡眠维持性失眠（p=0.002,部分等方差=0.52）。后一发现在随访的动觉测量仪（p=0.004,partial eta squared=0.32）夜间运动活动模式中得到了证实。更严重的睡眠维持性失眠与更严重的认知缺陷有关（径A p=<0.001,R平方=0.78;SDMT p=0.008,R平方=0.63;径B p=0.013,R平方=0.60），与更高的NfL水平有关（p=0.015,R平方=0.39）。纵向建模表明，睡眠阶段不稳定性产生于显现前的早期阶段，而睡眠维持性失眠则出现于接近表型转换的阶段。基线睡眠阶段不稳定性能够区分在研究期间表型转换的患者和仍处于表型转换前的患者（曲线下面积=0.81,p=0.024）。这些结果表明，发病前/早期 HD 的主要睡眠异常是睡眠阶段不稳定和睡眠维持性失眠，并表明前者具有预测疾病发病的价值，而后者则与疾病活动和认知障碍的增加有关。对这种关联的因果关系进行干预研究不仅能使 HD 患者受益，还有助于为更广泛的睡眠-神经变性领域提供基本的概念验证结果。
{"title":"A 12-year polysomnographic study in Huntingtons: sleep problems predict disease onset and severity","authors":"Zanna J Voysey, Anna OG Goodman, Lorraine Rogers, Jonathan A Holbrook, Alpar S Lazar, Roger A Barker","doi":"10.1101/2024.07.31.24311309","DOIUrl":"https://doi.org/10.1101/2024.07.31.24311309","url":null,"abstract":"Increasing evidence suggests that the sleep pathology associated with neurodegenerative diseases can in turn exacerbate both the cognitive deficits and underlying pathobiology of these conditions. Treating sleep may therefore bear significant, even disease-modifying, potential for these conditions, but how best and when to do so remains undetermined. Huntingtons Disease (HD), by virtue of being an autosomal-dominant neurodegenerative disease presenting in mid-life, presents a key model condition through which to advance this field. To date, however, there has been no clinical longitudinal study of sleep abnormalities in HD, and no robust interrogation of their association with disease onset, cognitive deficits and markers of disease activity. Here we present the first such study. HD gene carriers (n=28) and age- and sex-matched controls (n=21) were studied at baseline and 10- and 12-year follow up. All HD gene carriers were premanifest at baseline, and were stratified at follow up into prodromal/manifest and premanifest groups. Sleep abnormalities were assessed through two-night inpatient polysomnography (PSG) and two-week domiciliary actigraphy, and their association was explored against i)validated cognitive and affective outcomes (Montreal Cognitive Assessment, Trail A/B task, Symbol Digit Modalities Task [SDMT], Hopkins Verbal Learning Task [HVLT], Montgomery-Asberg Depression Rating Scale [MADRS]) and ii)serum neurofilament-light (NfL) levels. Statistical analysis incorporated cross-sectional ANCOVA, longitudinal repeated measures linear models and regressions adjusted for multiple confounders including disease stage. 15 HD gene carriers phenoconverted to prodromal/early manifest HD by study completion. At follow-up, these gene carriers showed more frequent sleep stage changes (p=<0.001,partial eta squared=0.62) and higher levels of sleep maintenance insomnia (p=0.002,partial eta squared=0.52). The latter finding was corroborated by nocturnal motor activity patterns on follow-up actigraphy (p=0.004,partial eta squared=0.32). Greater sleep maintenance insomnia was associated with greater cognitive deficits (Trail A p=<0.001,R squared=0.78;SDMT p=0.008,R squared=0.63;Trail B p=0.013,R squared=0.60) and higher levels of NfL (p=0.015,R squared=0.39). Longitudinal modelling suggested that sleep stage instability accrues from the early premanifest phase, whereas sleep maintenance insomnia emerges closer to phenoconversion. Baseline sleep stage instability was able to discriminate those who phenoconverted within the study period from those who remained premanifest (area under curve=0.81,p=0.024). These results demonstrate that the key sleep abnormalities of premanifest/early HD are sleep stage instability and sleep maintenance insomnia, and suggest that the former bears value in predicting disease onset, while the latter is associated with greater disease activity and cognitive deficits. Intervention studies to interrogate causation within th","PeriodicalId":501367,"journal":{"name":"medRxiv - Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141884906","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}
Pub Date : 2024-08-02DOI: 10.1101/2024.07.31.24311324
Jing Zhao, Huicong Niu, Yong Wang, Ning Yang, Min Chu, Xueyu Mao, Daosheng Wang
Background: Aggressive lipid-lowering therapy is recommended for patients with ischemic stroke; however, lipid paradox has been reported in several clinical studies. The mechanism of lipid paradox remains uncertain, and nutrition maybe one explanation. In this prospective cohort study, we explored the associations between baseline remnant cholesterol (RC) concentrations and clinical outcomes in patients with ischemic stroke, stratified by nutritional status. Materials and Methods: A total of 5257 patients with ischemic stroke were recruited for analysis. The Controlling Nutritional Status (CONUT) score was utilized to investigate the risk of malnutrition. Individuals were classified into 4 groups based on their CONUT score. Poor outcomes and all-cause mortality were compared among patients with varied nutritional status and RC levels. Results: Patients with moderate-severe malnutrition had the highest incidences of in-hospital complications, including pulmonary infection, renal dysfunction, and hemorrhagic transformation, and the highest rates of poor outcomes (61.3%, P?0.001) and all-cause mortality (32.8%, P?0.001) during the 3-month follow-up period. Baseline higher RC level was an independent protective factor of adverse clinical outcomes for patients with any degree of malnutrition, which was not observed in patients without malnutrition. In addition, compared with the moderate-severe malnourished with RC ?0.471 mmol/L, the adjusted ORs for poor outcomes and all-cause mortality were 0.805 (0.450?1.438) and 0.898 (0.502-1.607) for participants with 0.471-0.632 mmol/L, 0.259 (0.095-0.704) and 0.222 (0.061-0.810) for 0.633-0.868 mmol/L, and 0.160 (0.037?0.689) and 0.202 (0.042-0.967) for ? 0.869 mmol/L, prospectively. Conclusion: Lipid paradox was only observed in the malnourished patients with ischemic stroke. Strict lipid reduction therapy is still recommended for patients with ischemic stroke and good nutritional status. However, when treating patients at any risk of malnutrition, the improvement of nutritional status may be more crucial than aggressive lipid control.
{"title":"Elevated remnant cholesterol improves prognosis of patients with ischemic stroke and malnutrition: a cohort-based study","authors":"Jing Zhao, Huicong Niu, Yong Wang, Ning Yang, Min Chu, Xueyu Mao, Daosheng Wang","doi":"10.1101/2024.07.31.24311324","DOIUrl":"https://doi.org/10.1101/2024.07.31.24311324","url":null,"abstract":"Background: Aggressive lipid-lowering therapy is recommended for patients with ischemic stroke; however, lipid paradox has been reported in several clinical studies. The mechanism of lipid paradox remains uncertain, and nutrition maybe one explanation. In this prospective cohort study, we explored the associations between baseline remnant cholesterol (RC) concentrations and clinical outcomes in patients with ischemic stroke, stratified by nutritional status. Materials and Methods: A total of 5257 patients with ischemic stroke were recruited for analysis. The Controlling Nutritional Status (CONUT) score was utilized to investigate the risk of malnutrition. Individuals were classified into 4 groups based on their CONUT score. Poor outcomes and all-cause mortality were compared among patients with varied nutritional status and RC levels.\u0000Results: Patients with moderate-severe malnutrition had the highest incidences of in-hospital complications, including pulmonary infection, renal dysfunction, and hemorrhagic transformation, and the highest rates of poor outcomes (61.3%, P?0.001) and all-cause mortality (32.8%, P?0.001) during the 3-month follow-up period. Baseline higher RC level was an independent protective factor of adverse clinical outcomes for patients with any degree of malnutrition, which was not observed in patients without malnutrition. In addition, compared with the moderate-severe malnourished with RC ?0.471 mmol/L, the adjusted ORs for poor outcomes and all-cause mortality were 0.805 (0.450?1.438) and 0.898 (0.502-1.607) for participants with 0.471-0.632 mmol/L, 0.259 (0.095-0.704) and 0.222 (0.061-0.810) for 0.633-0.868 mmol/L, and 0.160 (0.037?0.689) and 0.202 (0.042-0.967) for ? 0.869 mmol/L, prospectively. Conclusion: Lipid paradox was only observed in the malnourished patients with ischemic stroke. Strict lipid reduction therapy is still recommended for patients with ischemic stroke and good nutritional status. However, when treating patients at any risk of malnutrition, the improvement of nutritional status may be more crucial than aggressive lipid control.","PeriodicalId":501367,"journal":{"name":"medRxiv - Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141884977","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}
Pub Date : 2024-08-02DOI: 10.1101/2024.08.01.24311353
Sara Pisani, Latha Velayudhan, Dag Aarsland, K Ray Chaudhuri, Clive Ballard, Dominic ffytche, Sagnik Bhattacharyya
Background: Cognitive deficits have been reported in Parkinson's Disease psychosis (PDP). Reduced dopamine transporter (DAT) binding ratio has also been associated with PDP. However, it remains unclear whether DAT striatal binding ratio (SBR) may contribute to worsening cognitive performance in PDP. Here, we examined this using data from the Parkinson's Progression Markers Initiative study. Methods: We analysed data from 408 PD patients, from baseline to year 4 follow up, and classified patients into PD with (PDP) and without psychosis (PDnP). DAT SBR was available from DaTSCAN imaging with 123 I-FP-CIT-SPECT. We examined all cognitive measures assessed at each time point, socio-demographics, neuropsychiatric and PD-specific symptoms were entered as covariates of interest. Results: PDP patients had lower DAT SBR compared to PDnP patients (b=-0.092, p=0.035) which remained significant after controlling for age, sex, and ethnicity. PDP patients also reported worse trajectory of task performance on MoCA (b=-0.238, p=0.001) and Symbol Digit Modality (b=-0.534, p=0.016) across four years compared to PDnP patients. Worsening of MoCA scores in PDP was independent of DAT SBR decline (interaction group * study years, b=-0.284, p=0.016; three-way interaction group*study years*DAT SBR, b=0.127, p=0.225). However, declining performance in Symbol Digit Modality was significantly associated with the decline in DAT SBR (three-way interaction group*study years*DAT SBR, b=0.683, p=0.028). Conclusion: Overall, longitudinal decline in striatal presynaptic dopamine function may underlie the greater longitudinal decline in performance in the symbol digit modality task that engages processing speed, associative learning and working memory in PD psychosis, whilst declining performance on MoCA seems unrelated to it. Whether striatal presynaptic dopamine changes explain accelerated longitudinal decline in other cognitive domains in people with PDP remains to be tested.
{"title":"Decline in striatal binding ratio associated with accelerated decline in performance on Symbol Digit Modality but not MoCA in Parkinson's disease psychosis","authors":"Sara Pisani, Latha Velayudhan, Dag Aarsland, K Ray Chaudhuri, Clive Ballard, Dominic ffytche, Sagnik Bhattacharyya","doi":"10.1101/2024.08.01.24311353","DOIUrl":"https://doi.org/10.1101/2024.08.01.24311353","url":null,"abstract":"Background: Cognitive deficits have been reported in Parkinson's Disease psychosis (PDP). Reduced dopamine transporter (DAT) binding ratio has also been associated with PDP. However, it remains unclear whether DAT striatal binding ratio (SBR) may contribute to worsening cognitive performance in PDP. Here, we examined this using data from the Parkinson's Progression Markers Initiative study.\u0000Methods: We analysed data from 408 PD patients, from baseline to year 4 follow up, and classified patients into PD with (PDP) and without psychosis (PDnP). DAT SBR was available from DaTSCAN imaging with <sup> 123 </sup>I-FP-CIT-SPECT. We examined all cognitive measures assessed at each time point, socio-demographics, neuropsychiatric and PD-specific symptoms were entered as covariates of interest. Results: PDP patients had lower DAT SBR compared to PDnP patients (b=-0.092, p=0.035) which remained significant after controlling for age, sex, and ethnicity. PDP patients also reported worse trajectory of task performance on MoCA (b=-0.238, p=0.001) and Symbol Digit Modality (b=-0.534, p=0.016) across four years compared to PDnP patients. Worsening of MoCA scores in PDP was independent of DAT SBR decline (interaction group * study years, b=-0.284, p=0.016; three-way interaction group*study years*DAT SBR, b=0.127, p=0.225). However, declining performance in Symbol Digit Modality was significantly associated with the decline in DAT SBR (three-way interaction group*study years*DAT SBR, b=0.683, p=0.028).\u0000Conclusion: Overall, longitudinal decline in striatal presynaptic dopamine function may underlie the greater longitudinal decline in performance in the symbol digit modality task that engages processing speed, associative learning and working memory in PD psychosis, whilst declining performance on MoCA seems unrelated to it. Whether striatal presynaptic dopamine changes explain accelerated longitudinal decline in other cognitive domains in people with PDP remains to be tested.","PeriodicalId":501367,"journal":{"name":"medRxiv - Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141884978","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}
Pub Date : 2024-08-01DOI: 10.1101/2024.07.31.24310616
William T O'Brien, James W Hickey, Steven Mutimer, Lauren J Evans, Blake D Colman, Becca Xie, Lauren P Giesler, Brendan P Major, Biswadev Mitra, Gershon Spitz, Terence J O'Brien, Sandy R Shultz, Stuart J McDonald
The diagnostic utility of blood glial fibrillary acidic protein (GFAP) in sport-related concussion (SRC) is unclear. This study measured serum GFAP at either 16-24 hours (h), 24-32h, or 36-52h post-SRC in 156 Australian football players and compared levels with 98 control players without SRC. Median GFAP levels were higher in SRC cases at 16-24h (124.7 pg/mL; p<0.001) and 24-32h (96.2 pg/mL; p<0.001) compared to controls (66.0 pg/mL), but not at 36-52h (62.8 pg/mL). GFAP had an area under the curve of 0.83 at 16-24h and 0.72 at 24-32h. Serum GFAP at 16-24h can be a useful aid in SRC diagnosis.
{"title":"Next-day Serum Glial Fibrillary Acidic Protein Levels to Aid Diagnosis of Sport-Related Concussion","authors":"William T O'Brien, James W Hickey, Steven Mutimer, Lauren J Evans, Blake D Colman, Becca Xie, Lauren P Giesler, Brendan P Major, Biswadev Mitra, Gershon Spitz, Terence J O'Brien, Sandy R Shultz, Stuart J McDonald","doi":"10.1101/2024.07.31.24310616","DOIUrl":"https://doi.org/10.1101/2024.07.31.24310616","url":null,"abstract":"The diagnostic utility of blood glial fibrillary acidic protein (GFAP) in sport-related concussion (SRC) is unclear. This study measured serum GFAP at either 16-24 hours (h), 24-32h, or 36-52h post-SRC in 156 Australian football players and compared levels with 98 control players without SRC. Median GFAP levels were higher in SRC cases at 16-24h (124.7 pg/mL; p<0.001) and 24-32h (96.2 pg/mL; p<0.001) compared to controls (66.0 pg/mL), but not at 36-52h (62.8 pg/mL). GFAP had an area under the curve of 0.83 at 16-24h and 0.72 at 24-32h. Serum GFAP at 16-24h can be a useful aid in SRC diagnosis.","PeriodicalId":501367,"journal":{"name":"medRxiv - Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141863420","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}
Pub Date : 2024-08-01DOI: 10.1101/2024.07.30.24311248
Jeffrey J. Iliff, Donald L. Elbert, Laurent Giovangrandi, Tarandeep Singh, Venky Venkatesh, Alejandro Corbellini, Robert M. Kaplan, Elizabeth Ludington, Kevin Yarasheski, Jeffrey Lowenkron, Carla VandeWeerd, Miranda M. Lim, Paul Dagum
Poor sleep is implicated in the development of Alzheimers disease (AD) pathology and cognitive impairment. The glymphatic system has been proposed as a link between sleep disruption and AD, and in animal models glymphatic impairment is sufficient to drive the development of AD pathology. It remains unknown whether the glymphatic system clears amyloid beta (Ab) and tau from the brain in humans. In a multi-site randomized crossover clinical trial (N=39), participants underwent overnight in-laboratory conditions of normal sleep and sleep deprivation following instrumentation that included a novel device to measure brain parenchymal resistance to glymphatic flow (RP) by transcranial multifrequency impedance spectroscopy and sleep electroencephalography (EEG). This study directly tested the hypothesis that sleep-active glymphatic clearance increases morning plasma AD biomarker levels. The primary outcomes were the change in plasma levels of AD biomarkers (Ab40, Ab42, np-tau181, np-tau217 and p-tau181) from evening to morning predicted by RP, sleep EEG features, and heart rate. We found that changes in RP, heart rate and EEG delta power predicted changes in Ab42 (p<0.001), np-tau181 (p=0.002), np-tau217 (p<0.001) and p-tau181 (p<0.001). The predicted changes replicated those from a multicompartment model based on published data on Ab; and tau efflux from brain to plasma. Our findings show that elements of sleep-active physiology, in particular decreased brain parenchymal resistance, facilitates the clearance of AD biomarkers to plasma, supporting a role for glymphatic clearance in these processes, and suggesting the enhancement of glymphatic function as a therapeutic target to reduce the development and progression of AD pathology in at-risk populations.
睡眠不足与阿尔茨海默病（AD）的病理发展和认知障碍有关。有人提出，甘油系统是睡眠中断与阿兹海默病之间的联系，在动物模型中，甘油系统受损足以导致阿兹海默病的病理发展。目前还不清楚人的肾上腺系统是否能清除大脑中的β淀粉样蛋白（Ab）和tau。在一项多地点随机交叉临床试验（N=39）中，参与者在实验室内接受了一夜的正常睡眠和睡眠剥夺，并使用了包括新型设备在内的仪器，通过经颅多频阻抗谱和睡眠脑电图（EEG）测量大脑实质对甘液流的阻力（RP）。这项研究直接测试了睡眠活动性甘油清除会增加早晨血浆中注意力缺失症生物标志物水平的假设。主要结果是根据RP、睡眠脑电图特征和心率预测从傍晚到清晨AD生物标志物（Ab40、Ab42、np-tau181、np-tau217和p-tau181）血浆水平的变化。我们发现，RP、心率和 EEG delta 功率的变化可预测 Ab42（p<0.001）、np-tau181（p=0.002）、np-tau217（p<0.001）和 p-tau181 （p<0.001）的变化。预测的变化与基于已发表的 Ab 和 tau 从大脑到血浆的外流数据的多室模型所预测的变化相同。我们的研究结果表明，睡眠活跃的生理要素，特别是脑实质阻力的降低，促进了AD生物标志物向血浆的清除，支持了血糖清除在这些过程中的作用，并建议将增强血糖功能作为治疗目标，以减少高危人群中AD病理的发展和恶化。
{"title":"The glymphatic system clears amyloid beta and tau from brain to plasma in humans","authors":"Jeffrey J. Iliff, Donald L. Elbert, Laurent Giovangrandi, Tarandeep Singh, Venky Venkatesh, Alejandro Corbellini, Robert M. Kaplan, Elizabeth Ludington, Kevin Yarasheski, Jeffrey Lowenkron, Carla VandeWeerd, Miranda M. Lim, Paul Dagum","doi":"10.1101/2024.07.30.24311248","DOIUrl":"https://doi.org/10.1101/2024.07.30.24311248","url":null,"abstract":"Poor sleep is implicated in the development of Alzheimers disease (AD) pathology and cognitive impairment. The glymphatic system has been proposed as a link between sleep disruption and AD, and in animal models glymphatic impairment is sufficient to drive the development of AD pathology. It remains unknown whether the glymphatic system clears amyloid beta (Ab) and tau from the brain in humans. In a multi-site randomized crossover clinical trial (N=39), participants underwent overnight in-laboratory conditions of normal sleep and sleep deprivation following instrumentation that included a novel device to measure brain parenchymal resistance to glymphatic flow (RP) by transcranial multifrequency impedance spectroscopy and sleep electroencephalography (EEG). This study directly tested the hypothesis that sleep-active glymphatic clearance increases morning plasma AD biomarker levels. The primary outcomes were the change in plasma levels of AD biomarkers (Ab40, Ab42, np-tau181, np-tau217 and p-tau181) from evening to morning predicted by RP, sleep EEG features, and heart rate. We found that changes in RP, heart rate and EEG delta power predicted changes in Ab42 (p<0.001), np-tau181 (p=0.002), np-tau217 (p<0.001) and p-tau181 (p<0.001). The predicted changes replicated those from a multicompartment model based on published data on Ab; and tau efflux from brain to plasma. Our findings show that elements of sleep-active physiology, in particular decreased brain parenchymal resistance, facilitates the clearance of AD biomarkers to plasma, supporting a role for glymphatic clearance in these processes, and suggesting the enhancement of glymphatic function as a therapeutic target to reduce the development and progression of AD pathology in at-risk populations.","PeriodicalId":501367,"journal":{"name":"medRxiv - Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141872712","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}
Pub Date : 2024-08-01DOI: 10.1101/2024.07.31.24311258
Iddo Magen, Hannah Marlene Kaneb, Maria Masnata, Nisha Pulimood, Anna Emde, Angela Genge, Eran Hornstein
The RNAse III DICER is essential for miRNA biogenesis. DICER activity is downregulated in sporadic and genetic forms of ALS. Accordingly, hundreds of miRNAs are broadly downregulated, and their mRNA targets are de-repressed. Enoxacin is a fluoroquinolone, which increases DICER activity and miRNA biogenesis. In an investigator-initiated, first-in-patient phase Ib/IIa study we tested Enoxacin safety and tolerability in patients with ALS and explored pharmacodynamic biomarkers for Enoxacin target engagement. Six patients with sporadic ALS were dosed with oral Enoxacin twice daily for 30 days. Patients did not experience any serious adverse events and completed the dosing period. Molecular analysis of cell-free miRNA in plasma and CSF revealed a global increase in plasma and CSF miRNA levels in all post-treatment time points, compared to baseline. Therefore, our study demonstrates that Enoxacin is tolerable and provides important evidence for in-patient target engagement. These results encourage testing Enoxacin efficacy in larger trials.
{"title":"A phase Ib/IIa study of Enoxacin in patients with ALS","authors":"Iddo Magen, Hannah Marlene Kaneb, Maria Masnata, Nisha Pulimood, Anna Emde, Angela Genge, Eran Hornstein","doi":"10.1101/2024.07.31.24311258","DOIUrl":"https://doi.org/10.1101/2024.07.31.24311258","url":null,"abstract":"The RNAse III DICER is essential for miRNA biogenesis. DICER activity is downregulated in sporadic and genetic forms of ALS. Accordingly, hundreds of miRNAs are broadly downregulated, and their mRNA targets are de-repressed. Enoxacin is a fluoroquinolone, which increases DICER activity and miRNA biogenesis. In an investigator-initiated, first-in-patient phase Ib/IIa study we tested Enoxacin safety and tolerability in patients with ALS and explored pharmacodynamic biomarkers for Enoxacin target engagement. Six patients with sporadic ALS were dosed with oral Enoxacin twice daily for 30 days. Patients did not experience any serious adverse events and completed the dosing period. Molecular analysis of cell-free miRNA in plasma and CSF revealed a global increase in plasma and CSF miRNA levels in all post-treatment time points, compared to baseline. Therefore, our study demonstrates that Enoxacin is tolerable and provides important evidence for in-patient target engagement. These results encourage testing Enoxacin efficacy in larger trials.","PeriodicalId":501367,"journal":{"name":"medRxiv - Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141863421","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}
Pub Date : 2024-07-31DOI: 10.1101/2024.07.29.24311199
Matthew Alexander Abikenari, Maria Leite
Thymic malignancies are rare cancer tumours of the thymus arising from thymic epithelial cells and are characterized by a highly diversified clinical phenotype, substantial histologic and morphologic heterogeneity, and frequent presentations of associated paraneoplastic autoimmune syndromes. Myasthenia Gravis (MG) is the most prevalent of such autoimmune conditions, presenting in roughly half of thymoma patients, and is associated with substantial hyperactivation of T lymphocytes, highly dysregulated negative and positive T lymphocyte selection, leading to a systemic imbalance of the immune system, and consequently aiding and abetting the manifestation of severe opportunistic infections and multiple autoimmune comorbidities such as Pure Red Cell Aplasia and Good's syndrome. Although the clinical, immunological and cytoarchitectural changes associated with thymomas have been increasingly elucidated in the contemporary literature, very few studies have interrogated the direct role of tumour staging and histological gradings on the occurrence and recurrence of infections and multiple autoimmune comorbidities. The current study aimed to interrogate the role of WHO thymoma classification criteria and Masaoka staging on the recurrence of severe opportunistic infections and the presentation of multiple paraneoplastic autoimmune syndromes post-thymectomy. The current study collected clinical and immunological data from 109 patients suffering from both MG and a pathologically proven thymoma. Statistical analysis of the collected data yielded significant associations between different stages of Masaoka grading and WHO classification on the number of autoimmune comorbidity and presence of severe recurrent infections, leading to the conclusion that early histological gradings and tumour infiltration patterns play a significant role in predicting future immunological behaviour, clinical outcomes, and susceptibility to recurrent infections. Future studies must further investigate the role of autoimmunity, its associated antibody expression profiles and thymic tissue pathology. Furthermore, novel therapeutics must further explore the role of emergent immunotherapeutics, such as adoptive cell therapies, as a viable patient-stratified treatment strategy for thymic malignancies.
胸腺恶性肿瘤是由胸腺上皮细胞引起的罕见的胸腺肿瘤，具有临床表型高度多样化、组织学和形态学异质性强以及经常出现相关的副肿瘤性自身免疫综合征等特点。胸腺癌肌萎缩症（MG）是此类自身免疫疾病中最常见的一种，约有一半的胸腺癌患者会出现这种症状，它与 T 淋巴细胞的过度活化、T 淋巴细胞阴性和阳性选择的高度失调有关，导致免疫系统的全身性失衡，从而助长了严重的机会性感染和多种自身免疫合并症（如纯红细胞增生症和古德综合征）的出现。尽管与胸腺瘤相关的临床、免疫学和细胞结构变化已在当代文献中得到越来越多的阐明，但很少有研究探讨肿瘤分期和组织学分级对感染和多种自身免疫合并症的发生和复发的直接作用。本研究旨在探讨世界卫生组织胸腺分类标准和正冈分期对胸腺切除术后严重机会性感染复发和多种副肿瘤自身免疫综合征的影响。本研究收集了109例同时患有MG和病理证实的胸腺瘤患者的临床和免疫学数据。对收集到的数据进行统计分析后发现，不同阶段的正冈分级和世卫组织分类与自身免疫合并症的数量和是否存在严重的复发性感染有显著关联，从而得出结论：早期组织学分级和肿瘤浸润模式在预测未来的免疫学行为、临床结果和复发性感染的易感性方面起着重要作用。未来的研究必须进一步探讨自身免疫、相关抗体表达谱和胸腺组织病理学的作用。此外，新型疗法必须进一步探索新兴免疫疗法的作用，如采用性细胞疗法，作为胸腺恶性肿瘤的一种可行的患者分层治疗策略。
{"title":"Immunological presentations and clinical features associated with Thymic Malignancies: The potential role of histological classifications and tumour grading on the future recurrence of opportunistic infections and paraneoplastic autoimmune conditions","authors":"Matthew Alexander Abikenari, Maria Leite","doi":"10.1101/2024.07.29.24311199","DOIUrl":"https://doi.org/10.1101/2024.07.29.24311199","url":null,"abstract":"Thymic malignancies are rare cancer tumours of the thymus arising from thymic epithelial cells and are\u0000characterized by a highly diversified clinical phenotype, substantial histologic and morphologic\u0000heterogeneity, and frequent presentations of associated paraneoplastic autoimmune syndromes.\u0000Myasthenia Gravis (MG) is the most prevalent of such autoimmune conditions, presenting in roughly half\u0000of thymoma patients, and is associated with substantial hyperactivation of T lymphocytes, highly\u0000dysregulated negative and positive T lymphocyte selection, leading to a systemic imbalance of the\u0000immune system, and consequently aiding and abetting the manifestation of severe opportunistic infections\u0000and multiple autoimmune comorbidities such as Pure Red Cell Aplasia and Good's syndrome. Although\u0000the clinical, immunological and cytoarchitectural changes associated with thymomas have been\u0000increasingly elucidated in the contemporary literature, very few studies have interrogated the direct role of\u0000tumour staging and histological gradings on the occurrence and recurrence of infections and multiple\u0000autoimmune comorbidities. The current study aimed to interrogate the role of WHO thymoma\u0000classification criteria and Masaoka staging on the recurrence of severe opportunistic infections and the\u0000presentation of multiple paraneoplastic autoimmune syndromes post-thymectomy. The current study\u0000collected clinical and immunological data from 109 patients suffering from both MG and a pathologically\u0000proven thymoma. Statistical analysis of the collected data yielded significant associations between\u0000different stages of Masaoka grading and WHO classification on the number of autoimmune comorbidity\u0000and presence of severe recurrent infections, leading to the conclusion that early histological gradings and\u0000tumour infiltration patterns play a significant role in predicting future immunological behaviour, clinical\u0000outcomes, and susceptibility to recurrent infections. Future studies must further investigate the role of\u0000autoimmunity, its associated antibody expression profiles and thymic tissue pathology. Furthermore,\u0000novel therapeutics must further explore the role of emergent immunotherapeutics, such as adoptive cell\u0000therapies, as a viable patient-stratified treatment strategy for thymic malignancies.","PeriodicalId":501367,"journal":{"name":"medRxiv - Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141872711","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}
Pub Date : 2024-07-31DOI: 10.1101/2024.07.29.24311181
Amanda N Szabo-Reed, Amber Watts, Eric Vidoni, Jonathan Mahnken, Angela Van Sciver, Katrina Finley, John Clutton, Rachel Holden, Mickeal Key, Jeff Burns
The health care system is insufficiently capitalizing on the benefits of physical exercise in Americas aging population. Few practical tools exist to help clinicians incorporate physical activity into their clinical care, while significant barriers limit older adults from initiating and maintaining exercise programs. The Lifestyle Empowerment for Alzheimers Prevention (LEAP! Rx) Program will use two forms of participant enrollment: direct physician referrals through electronic health records (EHR) and self-referrals to test the efficacy of delivering a community-based exercise and healthy lifestyle program to older adults. After referral into the program, participants will be randomized to receive the LEAP! Rx Program or be placed on a standard of care waitlist. The LEAP! Rx program will consist of a personalized and structured exercise program combined with lifestyle education and mobile-health (m-Health) monitoring. This includes a 12-week Empowerment phase with intensive coaching and supervised exercise training, followed by a 40-week Lifestyle phase with intermittent supervised exercise and coaching. Lifestyle education includes monthly, evidence-based classes on optimal aging. This study will examine 1) the efficacy of the LEAP!Rx Program on increasing and sustaining cardiorespiratory fitness, 2) test the effect of the LEAP! Rx Program on secondary outcome measures of chronic disease risk factors, including insulin resistance, body composition, and lipids, and 3) assess the implementation and scalability of the LEAP!Rx Program for clinicians and patients and package best practices in implementation manuals. If successful, this studys findings could potentially revolutionize future healthcare practices, providing a new and practical approach to aging and chronic disease prevention.
{"title":"Lifestyle Empowerment for Alzheimer's Prevention Prescribed by Physicians: Methods and Adaptations to COVID-19","authors":"Amanda N Szabo-Reed, Amber Watts, Eric Vidoni, Jonathan Mahnken, Angela Van Sciver, Katrina Finley, John Clutton, Rachel Holden, Mickeal Key, Jeff Burns","doi":"10.1101/2024.07.29.24311181","DOIUrl":"https://doi.org/10.1101/2024.07.29.24311181","url":null,"abstract":"The health care system is insufficiently capitalizing on the benefits of physical exercise in Americas aging population. Few practical tools exist to help clinicians incorporate physical activity into their clinical care, while significant barriers limit older adults from initiating and maintaining exercise programs. The Lifestyle Empowerment for Alzheimers Prevention (LEAP! Rx) Program will use two forms of participant enrollment: direct physician referrals through electronic health records (EHR) and self-referrals to test the efficacy of delivering a community-based exercise and healthy lifestyle program to older adults. After referral into the program, participants will be randomized to receive the LEAP! Rx Program or be placed on a standard of care waitlist. The LEAP! Rx program will consist of a personalized and structured exercise program combined with lifestyle education and mobile-health (m-Health) monitoring. This includes a 12-week Empowerment phase with intensive coaching and supervised exercise training, followed by a 40-week Lifestyle phase with intermittent supervised exercise and coaching. Lifestyle education includes monthly, evidence-based classes on optimal aging. This study will examine 1) the efficacy of the LEAP!Rx Program on increasing and sustaining cardiorespiratory fitness, 2) test the effect of the LEAP! Rx Program on secondary outcome measures of chronic disease risk factors, including insulin resistance, body composition, and lipids, and 3) assess the implementation and scalability of the LEAP!Rx Program for clinicians and patients and package best practices in implementation manuals. If successful, this studys findings could potentially revolutionize future healthcare practices, providing a new and practical approach to aging and chronic disease prevention.","PeriodicalId":501367,"journal":{"name":"medRxiv - Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141872710","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}
Pub Date : 2024-07-27DOI: 10.1101/2024.07.25.24310894
Ting Shen, Jacob W. Vogel, Vivianna M Van Deerlin, EunRan Suh, Laynie Dratch, Jeffrey S. Phillips, Lauren Massimo, Edward B. Lee, David J. Irwin, Corey T. McMillan
Cortical atrophy in behavioral variant frontotemporal degeneration (bvFTD) exhibits spatial heterogeneity across genetic subgroups, potentially driven by distinct biological mechanisms. Using an integrative imaging-transcriptomics approach, we identified disparate and shared transcriptomic signatures associated with cortical thickness in C9orf72, GRN or MAPT-related bvFTD. Genes associated with cortical thinning in GRN-bvFTD were implicated in neurotransmission, further supported by mapping synaptic density maps to cortical thickness maps. Previously identified genes linked to TDP-43 positive neurons were significantly overlapped with genes associated with C9orf72-bvFTD and GRN-bvFTD, but not MAPT-bvFTD providing specificity for our associations. C9orf72-bvFTD and GRN-bvFTD shared genes displaying consistent directionality of correlations with cortical thickness, while MAPT-bvFTD displayed more pronounced differences in transcriptomic signatures with opposing directionality. Overall, we identified disparate and shared genes tied to regional vulnerability with increased biological interpretation including overlap with synaptic density maps and pathologically-specific gene expression, illuminating intricate molecular underpinnings contributing to heterogeneities in bvFTD.
{"title":"Disparate and shared transcriptomic signatures associated with cortical atrophy in genetic bvFTD","authors":"Ting Shen, Jacob W. Vogel, Vivianna M Van Deerlin, EunRan Suh, Laynie Dratch, Jeffrey S. Phillips, Lauren Massimo, Edward B. Lee, David J. Irwin, Corey T. McMillan","doi":"10.1101/2024.07.25.24310894","DOIUrl":"https://doi.org/10.1101/2024.07.25.24310894","url":null,"abstract":"Cortical atrophy in behavioral variant frontotemporal degeneration (bvFTD) exhibits spatial heterogeneity across genetic subgroups, potentially driven by distinct biological mechanisms. Using an integrative imaging-transcriptomics approach, we identified disparate and shared transcriptomic signatures associated with cortical thickness in C9orf72, GRN or MAPT-related bvFTD. Genes associated with cortical thinning in GRN-bvFTD were implicated in neurotransmission, further supported by mapping synaptic density maps to cortical thickness maps. Previously identified genes linked to TDP-43 positive neurons were significantly overlapped with genes associated with C9orf72-bvFTD and GRN-bvFTD, but not MAPT-bvFTD providing specificity for our associations. C9orf72-bvFTD and GRN-bvFTD shared genes displaying consistent directionality of correlations with cortical thickness, while MAPT-bvFTD displayed more pronounced differences in transcriptomic signatures with opposing directionality. Overall, we identified disparate and shared genes tied to regional vulnerability with increased biological interpretation including overlap with synaptic density maps and pathologically-specific gene expression, illuminating intricate molecular underpinnings contributing to heterogeneities in bvFTD.","PeriodicalId":501367,"journal":{"name":"medRxiv - Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141779253","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}
Pub Date : 2024-07-27DOI: 10.1101/2024.07.25.24310396
Huifang E Wang, Borana Dollomaja, Jan Paul TRIEBKORN, Gian Marco Duma, Adam WILLIAMSON, Julia Makhalova, Jean-didier LEMARERECHAL, Fabrice BARTOLOMEI, Viktor Jirsa
Estimating the epileptogenic zone network (EZN) is an important part of the diagnosis of drug-resistant focal epilepsy and plays a pivotal role in treatment and intervention. Virtual brain twins based on personalized whole brain modeling provides a formal method for personalized diagnosis by integrating patient-specific brain topography with structural connectivity from anatomical neuroimaging such as MRI and dynamic activity from functional recordings such as EEG and stereo-EEG (SEEG). Seizures demonstrate rich spatial and temporal features in functional recordings, which can be exploited to estimate the EZN. Stimulation-induced seizures can provide important and complementary information. In our modeling process, we consider invasive SEEG stimulation as the most practical current approach, and temporal interference (TI) stimulation as a potential future approach for non-invasive diagnosis and treatment. This paper offers a virtual brain twin framework for EZN diagnosis based on stimulation-induced seizures. This framework estimates the EZN and validated the results on synthetic data with ground-truth. It provides an important methodological and conceptual basis for a series of ongoing scientific studies and clinical usage, which are specified in this paper. This framework also provides the necessary step to go from invasive to non-invasive diagnosis and treatment of drug-resistant focal epilepsy.
{"title":"Virtual brain twins for stimulation in epilepsy","authors":"Huifang E Wang, Borana Dollomaja, Jan Paul TRIEBKORN, Gian Marco Duma, Adam WILLIAMSON, Julia Makhalova, Jean-didier LEMARERECHAL, Fabrice BARTOLOMEI, Viktor Jirsa","doi":"10.1101/2024.07.25.24310396","DOIUrl":"https://doi.org/10.1101/2024.07.25.24310396","url":null,"abstract":"Estimating the epileptogenic zone network (EZN) is an important part of the diagnosis of drug-resistant focal epilepsy and plays a pivotal role in treatment and intervention. Virtual brain twins based on personalized whole brain modeling provides a formal method for personalized diagnosis by integrating patient-specific brain topography with structural connectivity from anatomical neuroimaging such as MRI and dynamic activity from functional recordings such as EEG and stereo-EEG (SEEG). Seizures demonstrate rich spatial and temporal features in functional recordings, which can be exploited to estimate the EZN. Stimulation-induced seizures can provide important and complementary information. In our modeling process, we consider invasive SEEG stimulation as the most practical current approach, and temporal interference (TI) stimulation as a potential future approach for non-invasive diagnosis and treatment. This paper offers a virtual brain twin framework for EZN diagnosis based on stimulation-induced seizures. This framework estimates the EZN and validated the results on synthetic data with ground-truth. It provides an important methodological and conceptual basis for a series of ongoing scientific studies and clinical usage, which are specified in this paper. This framework also provides the necessary step to go from invasive to non-invasive diagnosis and treatment of drug-resistant focal epilepsy.","PeriodicalId":501367,"journal":{"name":"medRxiv - Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141779250","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}
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