Spatial patterns of atrophy,hypometabolism, and amyloid deposition in Alzheimer's disease correspond to dissociable functional brain networks

Recent neuroimaging studies of Alzheimer's disease (AD) have emphasized topographical similarities between AD‐related brain changes and a prominent cortical association network called the default‐mode network (DMN). However, the specificity of distinct imaging abnormalities for the DMN compared to other intrinsic connectivity networks (ICNs) of the limbic and heteromodal association cortex has not yet been examined systematically. We assessed regional amyloid load using AV45‐PET, neuronal metabolism using FDG‐PET, and gray matter volume using structural MRI in 473 participants from the Alzheimer's Disease Neuroimaging Initiative, including preclinical, predementia, and clinically manifest AD stages. Complementary region‐of‐interest and voxel‐based analyses were used to assess disease stage‐ and modality‐specific changes within seven principle ICNs of the human brain as defined by a standardized functional connectivity atlas. Amyloid deposition in AD dementia showed a preference for the DMN, but high effect sizes were also observed for other neocortical ICNs, most notably the frontoparietal‐control network. Atrophic changes were most specific for an anterior limbic network, followed by the DMN, whereas other neocortical networks were relatively spared. Hypometabolism appeared to be a mixture of both amyloid‐ and atrophy‐related profiles. Similar patterns of modality‐dependent network specificity were also observed in the predementia and, for amyloid deposition, in the preclinical stage. These quantitative data confirm a high vulnerability of the DMN for multimodal imaging abnormalities in AD. However, rather than being selective for the DMN, imaging abnormalities more generally affect higher order cognitive networks and, importantly, the vulnerability profiles of these networks markedly differ for distinct aspects of AD pathology. Hum Brain Mapp 37:35–53, 2016. © 2015 Wiley Periodicals, Inc.     

The “silent” imprint of musical training

Playing a musical instrument at a professional level is a complex multimodal task requiring information integration between different brain regions supporting auditory, somatosensory, motor, and cognitive functions. These kinds of task‐specific activations are known to have a profound influence on both the functional and structural architecture of the human brain. However, until now, it is widely unknown whether this specific imprint of musical practice can still be detected during rest when no musical instrument is used. Therefore, we applied high‐density electroencephalography and evaluated whole‐brain functional connectivity as well as small‐world topologies (i.e., node degree) during resting state in a sample of 15 professional musicians and 15 nonmusicians. As expected, musicians demonstrate increased intra‐ and interhemispheric functional connectivity between those brain regions that are typically involved in music perception and production, such as the auditory, the sensorimotor, and prefrontal cortex as well as Broca's area. In addition, mean connectivity within this specific network was positively related to musical skill and the total number of training hours. Thus, we conclude that musical training distinctively shapes intrinsic functional network characteristics in such a manner that its signature can still be detected during a task‐free condition. Hum Brain Mapp 37:536–546, 2016. © 2015 Wiley Periodicals, Inc.     

Freezing of gait in Parkinson's disease is associated with altered functional brain connectivity

BackgroundPatients with Parkinson's disease (PD) may develop several gait disturbances during the course of illness and Freezing of gait (FOG) is one of them. Several neuroimaging studies have been conducted to identify the neural correlates of FOG but results have not been uniform. Resting state functional MRI (rs-fMRI) is relatively less explored in PD patients with FOG. This study aims to compare the whole brain resting state connectivity of PD patients with and without FOG using rs-fMRI.Methodsrs-fMRI was obtained for 28 PD patients (15 with and 13 patients without FOG) who were matched for various demographic and clinical characteristics. Seed to voxel analysis was performed at whole brain level and compared between the two groups.ResultsWhen compared to patients without FOG, the patients with FOG had reduced functional connectivity across multiple seeds. Major finding was reduced inter-hemispheric connectivity of left parietal opercular cortex with multiple regions of the brain primarily involving the primary somatosensory and auditory areas, which also negatively correlated with the FOGQ scores.ConclusionOur findings suggest that alterations in the resting state functional connectivity of the opercular parietal cortex may be one of the substrates of FOG. Reduced interhemispheric connectivity probably is the reason for impairment of control and coordination in bilateral leg movements while walking.     

The redox state of the alarmin HMGB1 is a pivotal factor in neuroinflammatory and microglial priming: A role for the NLRP3 inflammasome

The alarmin high mobility group box-1 (HMGB1) has been implicated as a key factor mediating neuroinflammatory processes. Recent findings suggest that the redox state of HMGB1 is a critical molecular feature of HMGB1 such that the reduced form (fr-HMGB1) is chemotactic, while the disulfide form (ds-HMGB1) is pro-inflammatory. The present study examined the neuroinflammatory effects of these molecular forms as well as the ability of these forms to prime the neuroinflammatory and microglial response to an immune challenge. To examine the neuroinflammatory effects of these molecular forms in vivo, animals were administered intra-cisterna magna (ICM) a single dose of fr-HMGB1 (10 μg), ds-HMGB1 (10 μg) or vehicle and basal pro-inflammatory effects were measured 2 and 24 h post-injection in hippocampus. Results of this initial experiment demonstrated that ds-HMGB1 increased hippocampal pro-inflammatory mediators at 2 h (NF-κBIα mRNA, NLRP3 mRNA and IL-1β protein) and 24 h (NF-κBIα mRNA, TNFα mRNA, and NLRP3 protein) after injection. fr-HMGB1 had no effect on these mediators. These neuroinflammatory effects of ds-HMGB1 suggested that ds-HMGB1 may function to prime the neuroinflammatory response to a subsequent immune challenge. To assess the neuroinflammatory priming effects of these molecular forms, animals were administered ICM a single dose of fr-HMGB1 (10 μg), ds-HMGB1 (10 μg) or vehicle and 24 h after injection, animals were challenged with LPS (10 μg/kg IP) or vehicle. Neuroinflammatory mediators and the sickness response (3, 8 and 24 h after injection) were measured 2 h after immune challenge. We found that ds-HMGB1 potentiated the neuroinflammatory (NF-κBIα mRNA, TNFα mRNA, IL-1β mRNA, IL-6 mRNA, NLRP3 mRNA and IL-1β protein) and sickness response (reduced social exploration) to LPS challenge. fr-HMGB1 failed to potentiate the neuroinflammatory response to LPS. To examine whether these molecular forms of HMGB1 directly induce neuroinflammatory effects in isolated microglia, whole brain microglia were isolated and treated with fr-HMGB1 (0, 1, 10, 100, or 1000 ng/ml) or ds-HMGB1 (0, 1, 10, 100, or 1000 ng/ml) for 4 h and pro-inflammatory mediators measured. To assess the effects of these molecular forms on microglia priming, whole brain microglia were pre-exposed to these forms of HMGB1 (0, 1, 10, 100, or 1000 ng/ml) and subsequently challenged with LPS (10 ng/ml). We found that ds-HMGB1 increased expression of NF-κBIα mRNA and NLRP3 mRNA in isolated microglia, and potentiated the microglial pro-inflammatory response (TNFα mRNA, IL-1β mRNA and IL-1β protein) to LPS. fr-HMGB1 failed to potentiate the microglial pro-inflammatory response to LPS. Consistent with prior reports, the present findings demonstrate that the disulfide form of HMGB1 not only potentiates the neuroinflammatory response to a subsequent immune challenge in vivo, but also potentiates the sickness response to that challenge. Moreover, the present findings demonstrate for the first time that ds-HMGB1 directly potentiates the microglia pro-inflammatory response to an immune challenge, a finding that parallels the effects of ds-HMGB1 in vivo. In addition, ds-HMGB1 induced expression of NLRP3 and NF-κBIα in vivo and in vitro suggesting that the NLRP3 inflammasome may play role in the priming effects of ds-HMGB1. Taken together, the present results suggest that the redox state of HMGB1 is a critical determinant of the priming properties of HMGB1 such that the disulfide form of HMGB1 induces a primed immunophenotype in the CNS, which may result in an exacerbated neuroinflammatory response upon exposure to a subsequent pro-inflammatory stimulus.     

Intrinsic functional connectivity of insular cortex and symptoms of sickness during acute experimental inflammation

Task-based fMRI has been used to study the effects of experimental inflammation on the human brain, but it remains unknown whether intrinsic connectivity in the brain at rest changes during a sickness response. Here, we investigated the effect of experimental inflammation on connectivity between areas relevant for monitoring of bodily states, motivation, and subjective symptoms of sickness. In a double-blind randomized controlled experiment, 52 healthy volunteers were injected with 0.6 ng/kg LPS (lipopolysaccharide) or placebo, and participated in a resting state fMRI experiment after approximately 2 h 45 min. Resting state fMRI data were available from 48 participants, of which 28 received LPS and 20 received placebo. Bilateral anterior and bilateral posterior insula sections were used as seed regions and connectivity with bilateral orbitofrontal and cingulate (anterior and middle) cortices was investigated. Back pain, headache and global sickness increased significantly after as compared to before LPS, while a non-significant trend was shown for increased nausea. Compared to placebo, LPS was followed by increased connectivity between left anterior insula and left midcingulate cortex. This connectivity was significantly correlated to increase in back pain after LPS and tended to be related to increased global sickness, but was not related to increased headache or nausea. LPS did not affect the connectivity from other insular seeds. In conclusion, the finding of increased functional connectivity between left anterior insula and middle cingulate cortex suggests a potential neurophysiological mechanism that can be further tested to understand the subjective feeling of malaise and discomfort during a sickness response.     

健脾清化方对CKD2～3期患者慢性微炎症状态的随机对照多中心研究

目的:研究健脾清化方对慢性肾脏疾病(CKD)2～3期脾虚湿热患者慢性微炎症状态的作用。方法:3个中心的随机对照临床研究,随机分成中药组和对照组,并设20例健康体检患者为正常组。对照组予西医常规治疗,中药组在对照组基础上加用健脾清化方。共随访8周,观察治疗前后血肌酐(Scr)、超敏C反应蛋白(hs-CRP)、白细胞介素-17(IL-17)、干扰素-γ(IFN-γ)的变化。结果:最终中药组有74例、对照组有73例完成研究。治疗前两组的hs-CRP、IL-17、IFN-γ比正常组显著升高(P<0.05)。8周的治疗后,中药组的Scr有显著下降(P<0.05)。中药组hs-CRP平均下降了26.4%(P<0.05),而对照组有上升的趋势。中药组IL-17平均下降了73.5%(P<0.05),对照组平均下降了25.6%。中药组IFN-γ平均下降了48.3%(P<0.05),而对照组平均下降了23.3%。结论:CKD2～3期的脾虚湿热患者存在慢性微炎症状态,健脾清化方能明显改善微炎症状态。     

人工发酵虫草菌粉对糖尿病大鼠肾脏IL-17、p38 MAPK和NF-κB表达的影响

目的: 探讨人工发酵虫草菌粉对糖尿病大鼠肾脏白细胞介素17（IL-17）、p38 MAPK和NF-κB表达的影响。方法:雄性SD大鼠45只,随机选择15只为正常对照组（NC组）,其余30只大鼠通过一次性尾静脉注射链脲佐菌素（STZ,45 mg/kg）诱导建立糖尿病模型,造模成功的28只大鼠随机分为糖尿病组（DM组）和人工发酵虫草菌粉治疗组（虫草组,1 g/(kg·d）,每组各14只。虫草组给予每日1次人工发酵虫草菌粉溶液灌胃,NC组和DM组给予等体积生理盐水灌胃。18周末取材。计算肾重指数,检测血尿素氮（BUN）、肌酐（Scr）、24 h尿微量白尿蛋白（24 h UMA）。HE染色观察肾脏组织形态学变化;Masson染色观察肾脏纤维化程度;电镜观察各组大鼠肾小球超微结构改变;免疫组化法比较各组大鼠肾脏IL-17、p38 MAPK、NF-κB的表达水平。结果:(1) DM组肾重指数、BUN、Scr、24 h UMA较NC组明显升高,虫草组肾重指数、BUN、Scr、24 h UMA较DM组明显降低。(2) DM组肾脏纤维化明显,虫草组大鼠肾脏纤维化较DM组明显减轻。(3)电镜下,DM组大鼠肾小球毛细血管基底膜增厚,部分足细胞突起融合,系膜细胞增生;虫草组大鼠肾小球病变较DM组明显减轻。(4) DM组肾脏IL-17、p38 MAPK、NF-κB表达均显著上升,人工发酵虫草菌粉干预降低了肾脏IL-17、p38 MAPK、NF-κB的表达。结论:肾脏IL-17、p38 MAPK和NF-κB表达增多在糖尿病肾病发病过程中起到重要作用。人工发酵虫草菌粉可能通过减少肾脏IL-17、p38 MAPK、NF-κB的表达来改善糖尿病肾病。     

芒针透刺督脉组穴配合隔姜灸治疗脑卒中后睡眠障碍疗效及机制研究

目的:以芒针透刺督脉组穴配合隔姜灸对脑卒中后睡眠障碍患者进行干预治疗,观察患者睡眠改善情况及血清5-羟色胺(5-HT)、去甲肾上腺素(NA)和乙酰胆碱(Ach)水平变化,并分析其机制。方法:将同期收治的76例脑卒中后睡眠障碍患者采用随机数字表法分为观察组与对照组各38例。两组均给予脑卒中后常规西医康复治疗,在此基础上对照组辅以传统针灸治疗,观察组采用芒针透刺督脉组穴配合隔姜灸治疗,均连续治疗8周。治疗前后分别测定两组匹兹堡睡眠质量指数(PSQI)、睡眠状况自评量表(SSRS)、美国国立卫生研究院卒中量表(NIHSS)评分,据以计算睡眠障碍治疗总有效率;检测两组血清5-HT、NA和Ach水平,并观察有无不良反应。结果:两组治疗后PSQI、SSRS、NIHSS评分均较治疗前明显降低(P<0.05),且观察组治疗后各评分均明显低于对照组(P<0.05);观察组和对照组睡眠障碍治疗总有效率分别为92.11%、76.38%,两组比较差异有统计学意义(P<0.05);两组治疗后血清5-HT、NA、Ach水平均较治疗前明显提高(P<0.05),且观察组治疗后各指标均明显高于对照组(P<0.05);两组在治疗期间均未发生明显不良反应。结论:芒针透刺督脉组穴配合隔姜灸治疗脑卒中后睡眠障碍安全有效,可明显改善患者预后,机制可能与上调神经递质水平有关。     

中期妊娠胎盘前置状态引产剖宫产分娩影响因素分析

目的探讨中期妊娠胎盘前置状态引产分娩方式的相关影响因素。方法回顾性分析我院2012～2018年中期妊娠胎盘前置状态合并死胎或胎儿畸形的引产病例共51例,按分娩方式将其分为阴道分娩组和剖宫产组,比较两组间年龄、剖宫产史、孕次、产次、分娩孕周、胎盘覆盖宫颈内口范围、伴发胎盘植入、羊水量的差异。将单因素分析中具有统计学意义的变量(既往剖宫产史、胎盘覆盖宫颈内口范围、伴发胎盘植入)为自变量,拟合多因素Logistic回归方程,探讨胎盘前置状态引产剖宫产分娩的相关危险因素。结果 (1)阴道分娩组和剖宫产组比较,两组间既往剖宫产史、胎盘覆盖宫颈内口范围、伴发胎盘植入之间比较,差异均有统计学意义。(2)多因素Logistic回归分析显示,既往剖宫产史、伴发胎盘植入是剖宫产分娩的危险因素。与未植入比较,胎盘植入者剖宫产的危险度是其13.333倍;既往有剖宫产史者本次剖宫产的危险度是无剖宫产史者的8.727倍。结论胎盘前置状态中期妊娠引产,合并既往剖宫产史及胎盘植入者,其剖宫产分娩的危险度增加。     

综合护理干预对糖尿病患者心理状态及护理满意度的影响

目的探讨综合护理干预对糖尿病患者心理状态及护理满意度的影响。方法选取2017年12月～2018年12月我院收治的80例糖尿病患者作为研究对象,均为2型糖尿病,随机分为观察组与对照组,每组40例。两组患者均予以降糖药物进行治疗,同时分别采取不同的护理方法,其中对照组采取常规对症护理,观察组实施综合护理干预,观察两组患者的焦虑、抑郁评分及护理满意度。结果两组患者干预前的焦虑及抑郁心理评分比较,差异无统计学意义(P0.05);干预后观察组的焦虑及抑郁心理评分明显低于干预前及对照组,差异有统计学意义(P0.05),观察组患者治疗的总满意率为95.00%,对照组的总满意率为70.00%,两组护理总满意度对比,差异有统计学意义(P0.05)。结论对糖尿病患者在对症治疗的同时配合综合护理干预措施,有利于缓解患者的焦虑、紧张、抑郁及烦躁等负性心理,提高患者的护理满意度,改善护患关系,值得广泛推广和应用。