prodromal symptoms

前驱症状
  • 文章类型: Journal Article
    背景:越来越多的证据表明,空间导航的损害,方向和记忆可能代表了阿尔茨海默病(AD)的最早特征之一,在其他认知领域的先前缺陷。这与与空间处理有关的颞叶和顶叶大脑区域的早期病理性tau和淀粉样蛋白沉积一致。然而,目前尚不清楚哪些指标和空间行为可以区分高风险,临床前或前驱AD个体,和ii)可以用适合未来在临床实践中大规模部署的数字设备捕获。我们通过系统回顾来解决这一知识差距。
    方法:按照PRISMA指南搜索两个数据库(PubMed/WebofScience)。不同痴呆类型的医学副标题关键词与前驱结合,临床前和遗传或疾病危险因素术语。我们纳入了直到2022年10月发表的研究,这些研究收集了以自我为中心或以分配为中心的处理的数字或物理客观测量(寻路,定位,参考框架平移,路线学习或路径整合)。我们排除了其他疾病或痴呆症的诊断,无生物标志物的MCI横断面研究,年轻人,案例研究,介入研究或没有适当控制的研究。
    结果:从316篇确定的摘要中纳入25篇文章。没有人调查非AD痴呆症。从38个不同的任务中提取了131个指标,其中31位数字(81%)。82个指标显示了痴呆前AD组的分化(63%)。我们将这些统一为21个不同的汇总指标,涵盖了主动或被动跟踪的空间行为的四个领域。在所有域中,记录导航效率下降的指标(即寻找目标所需的距离或时间)和准确性(即与目标的距离或角度)的报告频率最高,但自我中心的前驱分化优于临床前组。用于日常GPS数据的路径集成和被动跟踪的度量很有希望,但相对不足。
    结论:对于未来的临床应用,空间测试将需要对已建立的疾病标志物进行标准化和验证。这些审查数据将为选择数字工具提供信息,以评估处于风险中的空间行为,临床前和前驱AD人群作为EDoN计划的一部分。
    BACKGROUND: Increasing evidence suggests that impairments of spatial navigation, orientation and memory may represent one of the earliest features Alzheimer\'s disease (AD), preceding deficits in other cognitive domains. This is consistent with early pathological tau and amyloid deposition in temporal and parietal brain regions implicated in spatial processing. However, it remains unclear which metrics and spatial behaviours can i) differentiate high-risk, preclinical or prodromal AD individuals, and ii) may be captured with digital devices suitable for future deployment at scale in clinical practice. We addressed this knowledge gap with a systematic review.
    METHODS: Two databases (PubMed/Web of Science) were searched following PRISMA guidelines. Medical subheading keywords for different dementia types were combined with prodromal, preclinical and genetic or disorder risk factor terms. We included studies published until October 2022 that collected digital or physical objective measures of egocentric or allocentric processing (wayfinding, orientation, reference frame translation, route learning or path integration). We excluded diagnoses of other conditions or dementia, cross-sectional MCI studies without biomarkers, young adults, case studies, interventional studies or studies without appropriate controls.
    RESULTS: 25 articles were included from 316 identified abstracts. None investigated non-AD dementias. 131 metrics were extracted from 38 different tasks, of which 31 where digital (81%). 82 metrics showed differentiation of predementia AD groups (63%). We harmonised these into 21 distinct summary metrics covering four domains of active or passively tracked spatial behaviours. Across all domains, metrics capturing decreased navigation efficiency (i.e. distance or time required to find goals) and accuracy (i.e. distance or angle from goal) were most frequently reported, but egocentric better differentiated prodromal than preclinical groups. Metrics for path integration and passive tracking of everyday GPS data were promising but relatively under-explored.
    CONCLUSIONS: For future clinical use, spatial tests will require standardisation and validation against established markers of disease. These review data will inform the selection of digital tools to assess spatial behaviours in at-risk, preclinical and prodromal AD populations as part of the EDoN Initiative.
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  • 文章类型: Journal Article
    BACKGROUND: The existing research has mainly focused on exploring how the duration of untreated psychosis effects the further course of the disease. By contrast, the duration of an untreated illness (DUI) in youth depression and its impact on the further course of the disease has remained scarcely investigated.
    OBJECTIVE: The current study aims to determine how the duration of untreated illness affects the severity of the symptoms during the first depressive episode and the degree to which the symptoms are reduced after treatment.
    METHODS: Fifty-two young male patients (15-29 years old) were examined. First, they were hospitalized with a severe without psychotic symptoms (F32.2) and moderate (F32.1) depressive episode. The Hamilton Depression Rating Scale (HDRS), the Scale of Prodromal Symptoms (SOPS), and the Scale for Assessment of Negative Symptoms (SANS) were used to achieve the research goals. The examination was conducted twice at the time of patient admission to the hospital and before discharge. Our statistical analysis was carried out with the Statistica 12 software. The Mann-Whitney U test was used to compare the differences between two independent groups. The Spearman\'s rank correlation coefficient was used to uncover any correlation between how long the illness has remained untreated and the severity of its clinical symptoms.
    RESULTS: All patients were hospitalized at the first depressive episode. The average duration of an untreated illness was 35.8±17.0 months. The patients were divided into two groups: the first group (59.6%, n=31), with a duration of the untreated illness of more than 36 months, and the second group (40.4%, n=21), with a duration of the untreated illness of less than 36 months. A cross-group comparison between the participants showed that the reduction of HDRS scores was significantly higher in the second group (p=0.019) at the time of discharge, with no differences in the severity of depressive symptoms (p=0.544) at the time of admission. Comorbidity was detected in 83.9% of the patients in the first group and in 42.9% of the patients in the second group. A greater therapy effectiveness was found to exist in the second group, as the depressive symptoms score on the HDRS scale (p=0.016; U=196.0) and prodromal symptoms score on the SOPS disorganization subscale (p=0.046; U=218.0) were found to have been reduced significantly.
    CONCLUSIONS: The study showed that DUI has an impact on the reduction of depressive, negative symptoms and symptoms of disorganization in youth patients at the first depressive episode. A high level of comorbidity has been uncovered, confirming that a variety of non-psychotic and psychotic disorders in youth manifest themselves in depression at a prodromal stage, causing difficulties in establishing diagnoses and requiring subsequent verification. Future research might need to focus on exploring depressive symptoms as predictors of mental disorders in youth patients.
    UNASSIGNED: В настоящее время большинство исследований сфокусированы на изучении влияния длительности нелеченого психоза на дальнейшее течение заболевания. В отношении длительности нелеченого заболевания при депрессии таких работ значительно меньше.
    UNASSIGNED: Целью данного исследования является: установить влияние длительности нелеченого заболевания на тяжесть симптомов депрессии, на степень их редукции за время лечения.
    UNASSIGNED: Обследованы 52 больных мужского пола 15–29 лет, впервые госпитализированных по поводу депрессивного эпизода тяжелой степени без психотических симптомов (F32.2) и средней степени тяжести (F32.1). Применялись Шкала оценки депрессивных симптомов (HDRS), Шкала оценки продромальных симптомов (SOPS) и Шкала оценки негативных симптомов (SANS). Обследование проводилось дважды: на момент поступления пациента в стационар и на этапе редукции психопатологических расстройств перед выпиской. Статистический анализ проводился с помощью программы Statistica 12. Для сравнения различий между двумя независимыми группами применялся непараметрический метод Манна — Уитни и ранговый коэффициент Спирмена для оценки взаимосвязей между длительностью нелеченного заболевания и тяжестью клинических симптомов.
    UNASSIGNED: Выборка включала больных, впервые госпитализированных с диагнозом «Депрессивный эпизод», средняя длительность нелеченого заболевания составила 35.8±17.0 месяцев. Пациенты были разделены на две группы: 1 группа (59.6%, n=31) с длительностью нелеченого заболевания более 36 месяцев, 2 группа (40.4%, n=21) — менее 36 месяцев. Межгрупповые сравнения показали, что редукция баллов по шкале HDRS к моменту выписки была значительно выше во второй группе (р=0.019) при отсутствии различий по степени выраженности депрессии при поступлении (р=0.544). Коморбидность отмечалась у 83.9% пациентов первой группы и у 42.9% — у второй. Лучший эффект терапии был установлен у больных второй группы по степени выраженности депрессивных симптомов (p=0.016; U=196.0) и продромальных симптомов, оцененных по подшкале симптомов дезорганизации шкалы SOPS (p=0.046; U=218.0) при выписке.
    UNASSIGNED: Исследование показало влияние длительности нелеченого заболевания на степень редукции депрессивных, негативных симптомов и симптомов дезорганизации у молодых людей с первым депрессивным эпизодом. Также была установлена большая степень коморбидности, подтверждающая, что различные непсихотические психические расстройства, а также психотические заболевания на продромальных стадиях могут проявляться депрессивной симптоматикой, что затрудняет диагностику юношеских депрессий и требует последующей верификации диагноза. Будущие исследования должны быть направлены на определение предикторной значимости юношеских депрессий в отношении развития психических расстройств в юношеском возрасте.
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  • 文章类型: Journal Article
    背景:阿尔茨海默病(AD)患者表现出与临床症状相关的丘脑结构改变。然而,考虑到大脑结构的解剖复杂性,目前尚不清楚萎缩是否会影响特定的丘脑核,并从前驱阶段调节临床进展,被称为轻度认知障碍(MCI),完整的AD。
    目的:为了表征整个AD光谱中不同丘脑核的结构完整性,测试转换为AD的MCI患者(c-MCI)与保持稳定的患者(s-MCI)相比是否显示出独特的丘脑结构改变模式。
    方法:研究AD光谱中不同丘脑核体积特征的组间差异。
    方法:AD的前驱期和临床分期。
    方法:我们分析了来自84名健康对照受试者(HC)的数据,58名MCI患者和102名AD患者。数据集从AD神经成像计划(ADNI-3)数据库获得。根据患者在诊断后48个月内是否保持稳定(s-MCI,n=22)或进展为AD(s-MCI,n=36),将MCI组进一步分为两个亚组。
    方法:多变量方差分析(MANOVA)评估了从磁共振(MR)图像获得的不同丘脑核的体积特征的组差异。逐步判别函数分析确定了哪个特征最有效地预测了向AD的转化。通过接收器工作特性方法评估了相应的预测性能。
    结果:与HC相比,AD和c-MCI患者显示丘脑核的广泛性萎缩。相比之下,在s-MCI和HC受试者之间没有观察到显著的结构差异.与s-MCI相比,c-MCI个体显示出细胞核的显着萎缩,并且在前腹核和后背核中有明显萎缩的趋势。判别函数分析证实了细胞核是AD转化的重要预测因子,灵敏度为0.73,特异性为0.69。
    结论:根据对AD患者进行的精液验尸研究提出的核重组的病理生理相关性,我们证实了该细胞核作为AD临床进展的关键枢纽的关键作用.我们还提出了一个理论模型来解释皮质下脑网络在疾病过程中不断发展的功能障碍。
    BACKGROUND: Patients with Alzheimer\'s Disease (AD) exhibit structural alterations of the thalamus that correlate with clinical symptoms. However, given the anatomical complexity of this brain structure, it is still unclear whether atrophy affects specific thalamic nuclei and modulates the clinical progression from a prodromal stage, known as Mild Cognitive Impairment (MCI), to full-fledged AD.
    OBJECTIVE: To characterize the structural integrity of distinct thalamic nuclei across the AD spectrum, testing whether MCI patients who convert to AD (c-MCI) show a distinctive pattern of thalamic structural alterations compared to patients who remain stable (s-MCI).
    METHODS: Investigating between-group differences in the volumetric features of distinct thalamic nuclei across the AD spectrum.
    METHODS: Prodromal and clinical stages of AD.
    METHODS: We analyzed data from 84 healthy control subjects (HC), 58 individuals with MCI, and 102 AD patients. The dataset was obtained from the AD Neuroimaging Initiative (ADNI-3) database. The MCI group was further divided into two subgroups depending on whether patients remained stable (s-MCI, n=22) or progressed to AD (s-MCI, n=36) in the 48 months following the diagnosis.
    METHODS: A multivariate analysis of variance (MANOVA) assessed group differences in the volumetric features of distinct thalamic nuclei obtained from magnetic resonance (MR) images. A stepwise discriminant function analysis identified which feature most effectively predicted the conversion to AD. The corresponding predictive performance was evaluated through a Receiver Operating Characteristic approach.
    RESULTS: AD and c-MCI patients showed generalized atrophy of thalamic nuclei compared to HC. In contrast, no significant structural differences were observed between s-MCI and HC subjects. Compared to s-MCI, c-MCI individuals displayed significant atrophy of the nucleus reuniens and a trend toward significant atrophy in the anteroventral and laterodorsal nuclei. The discriminant function analysis confirmed the nucleus reuniens as a significant predictor of AD conversion, with a sensitivity of 0.73 and a specificity of 0.69.
    CONCLUSIONS: In line with the pathophysiological relevance of the nucleus reuniens proposed by seminal post-mortem studies on patients with AD, we confirm the pivotal role of this nucleus as a critical hub in the clinical progression to AD. We also propose a theoretical model to explain the evolving dysfunction of subcortical brain networks in the disease process.
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  • 文章类型: Journal Article
    背景:在较小的队列研究中,默认模式和额叶控制网络的更强静息状态功能连接与阿尔茨海默病相关病理和神经变性的认知弹性相关。
    目的:我们研究了这些网络是否与β-淀粉样蛋白(Aβ)的AD生物标志物的纵向CR相关。
    方法:纵向混合。
    方法:无症状阿尔茨海默病(A4)的抗淀粉样蛋白治疗研究及其自然史观察臂,淀粉样蛋白风险和神经变性的纵向评估(LEARN)研究。
    方法:1,021名认知未受损的老年人的样本(平均年龄=71.2岁[SD=4.7岁],61%的女性,42%APOEε4携带者,52%Aβ阳性)。
    方法:在平均5.4年的随访期(SD=2年)内评估总体认知表现(临床前阿尔茨海默病认知综合)。根据功能磁共振成像和PET估计皮质Aβ和功能连通性(左和右额顶控制和默认模式网络),分别,在基线。协变量包括基线年龄,APOEε4载波状态,多年的教育,调整后的灰质体积,头部运动,研究组,累积治疗暴露,和认知测试版本。
    结果:混合效应模型显示,左额顶控制网络的功能连接调节了Aβ对认知变化的负面影响(p=0.025),因此更强的连接与Aβ相关的认知下降减少有关。
    结论:我们的结果证明了功能性连接在临床前AD中的潜在保护作用,因此,该网络中更强的连通性与较慢的Aβ相关认知衰退有关。
    BACKGROUND: Stronger resting-state functional connectivity of the default mode and frontoparietal control networks has been associated with cognitive resilience to Alzheimer\'s disease related pathology and neurodegeneration in smaller cohort studies.
    OBJECTIVE: We investigated whether these networks are associated with longitudinal CR to AD biomarkers of beta-amyloid (Aβ).
    METHODS: Longitudinal mixed.
    METHODS: The Anti-Amyloid Treatment in Asymptomatic Alzheimer\'s Disease (A4) study and its natural history observation arm, the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study.
    METHODS: A sample of 1,021 cognitively unimpaired older adults (mean age = 71.2 years [SD = 4.7 years], 61% women, 42% APOEε4 carriers, 52% Aβ positive).
    METHODS: Global cognitive performance (Preclinical Alzheimer\'s Cognitive Composite) was assessed over an average 5.4 year follow-up period (SD = 2 years). Cortical Aβ and functional connectivity (left and right frontoparietal control and default mode networks) were estimated from fMRI and PET, respectively, at baseline. Covariates included baseline age, APOEε4 carrier status, years of education, adjusted gray matter volume, head motion, study group, cumulative treatment exposure, and cognitive test version.
    RESULTS: Mixed effects models revealed that functional connectivity of the left frontoparietal control network moderated the negative effect of Aβ on cognitive change (p = .025) such that stronger connectivity was associated with reduced Aβ-related cognitive decline.
    CONCLUSIONS: Our results demonstrate a potential protective effect of functional connectivity in preclinical AD, such that stronger connectivity in this network is associated with slower Aβ-related cognitive decline.
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  • 文章类型: Journal Article
    背景:参与者在临床试验中停止研究治疗可能会导致试验效力不足,在统计分析中产生偏差,和限制研究结果的可解释性。因此,在整个研究持续时间内将参与者保留在临床试验中与参与者招募一样重要。
    目的:本分析旨在确定在无症状AD(A4)研究中抗淀粉样蛋白治疗的盲期,参与者的随机化前特征与过早停药的相关性。
    方法:所有A4试验的随机参与者都被归类为在研究的盲期由于任何原因而过早停止研究(退出)或完成治疗研究的盲期(完成者)。
    方法:该试验在美国67个研究中心进行,加拿大,日本和澳大利亚通过全球COVID-19大流行。
    方法:样本由所有1169名A4试验随机参与者组成。
    方法:预随机化人口统计,临床,使用单变量广义线性混合模型(GLMM)评估淀粉样蛋白PET和研究中止的遗传预测因子,以中止状态为二元结果,每个预测因子作为固定效应,和站点作为随机效应,以解释试验中研究站点之间的差异。然后将在p<0.10时显著的特征包括在多变量GLMM中。
    结果:在随机参与者中,339(29%)在盲期终止研究(试验中的中位随访时间:759天)。从多变量分析来看,研究中止的两个主要预测因素是筛查状态-特质焦虑量表(STAI)评分(OR=1.07[95CI=1.02;1.12];p=0.002)和年龄(OR=1.06[95CI=1.03;1.09];p<0.001).有痴呆家族史(OR=0.75[95CI=0.55;1.01];p=0.063)和APOEε4携带者(OR=0.79[95CI=0.6;1.04];p=0.094)的参与者不太可能退出研究。与协会是微不足道的。在这些分析中,性别,种族和民族,认知评分和淀粉样蛋白/tauPET评分与研究退出无关.
    结论:在A4试验中,年龄较大的参与者和通过STAI测量的基线焦虑水平较高的参与者更有可能中止,而有痴呆家族史或APOEε4携带者退出的可能性较小.这些发现对未来的临床前试验设计和选择过程有直接的影响,以确定那些有最大脱落风险的个体,并为研究团队提供信息,以制定AD预防研究中的有效选择和保留策略。
    BACKGROUND: Participant discontinuation from study treatment in a clinical trial can leave a trial underpowered, produce bias in statistical analysis, and limit interpretability of study results. Retaining participants in clinical trials for the full study duration is therefore as important as participant recruitment.
    OBJECTIVE: This analysis aims to identify associations of pre-randomization characteristics of participants with premature discontinuation during the blinded phase of the Anti-Amyloid treatment in Asymptomatic AD (A4) Study.
    METHODS: All A4 trial randomized participants were classified as having prematurely discontinued study during the blinded period of the study for any reason (dropouts) or completed the blinded phase of the study on treatment (completers).
    METHODS: The trial was conducted across 67 study sites in the United States, Canada, Japan and Australia through the global COVID-19 pandemic.
    METHODS: The sample consisted of all 1169 A4 trial randomized participants.
    METHODS: Pre-randomization demographic, clinical, amyloid PET and genetic predictors of study discontinuation were evaluated using a univariate generalized linear mixed model (GLMM), with discontinuation status as the binary outcome, each predictor as a fixed effect, and site as a random effect to account for differences among study sites in the trial. Characteristics significant at p<0.10 were then included in a multivariable GLMM.
    RESULTS: Among randomized participants, 339 (29%) discontinued the study during the blinded period (median follow-up time in trial: 759 days). From the multivariable analysis, the two main predictors of study discontinuation were screening State-Trait Anxiety Inventory (STAI) scores (OR = 1.07 [95%CI = 1.02; 1.12]; p=0.002) and age (OR = 1.06 [95%CI = 1.03; 1.09]; p<0.001). Participants with a family history of dementia (OR = 0.75 [95%CI = 0.55; 1.01]; p=0.063) and APOE ε4 carriers (OR = 0.79 [95%CI = 0.6; 1.04]; p=0.094) were less likely to discontinue from the study, with the association being marginally significant. In these analyses, sex, race and ethnicity, cognitive scores and amyloid/tau PET scores were not associated with study dropout.
    CONCLUSIONS: In the A4 trial, older participants and those with higher levels of anxiety at baseline as measured by the STAI were more likely to discontinue while those who had a family history of dementia or were APOE ε4 carriers were less likely to drop out. These findings have direct implications for future preclinical trial design and selection processes to identify those individuals at greatest risk of dropout and provide information to the study team to develop effective selection and retention strategies in AD prevention studies.
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  • 文章类型: Journal Article
    背景:MRI上可见的白质高强度(WMH)体积增加是阿尔茨海默病(AD)的常见发现。我们假设临床前AD中的WMH与表现为微出血(MCH)的晚期血管淀粉样变性有关。
    目的:1)评估基线WMH体积与基线MCH之间的关系。2)评估A4试验双盲阶段纵向WMH积累与末次MRIMCH之间的关系。
    方法:多中心,随机化,双盲,安慰剂对照,在临床前AD患者中,在4.5年内,每4周一次输注solanezumab与安慰剂进行比较的3期研究。定义为在临床上明显的认知障碍阶段之前有脑淀粉样蛋白升高的证据,具有可选的开放标签扩展期限。
    方法:抗淀粉样蛋白治疗无症状阿尔茨海默病(A4)研究。
    方法:1157名认知未受损的老年人(平均年龄=71.9岁[SD=4.8岁],59%的妇女,59%APOEε4携带者)。
    方法:使用线性回归模型来评估基线MCH量(0、1、2)对WMH体积的影响。线性混合效应模型用于评估末次MRIMCH对纵向WMH的影响。所有模型都校正了年龄,性别,灰质体积,皮质淀粉样蛋白PET,APOEε4状态,和治疗组。
    结果:与没有MCH的个体相比,具有一个以上MCH的个体的基线WMH体积更大(t=4.8,p<0.001)。在最后一次MRI中,具有一个(t=2.3,p=0.025)和一个以上MCH(t=6.7,p<0.001)的个体中WMH的纵向增加大于没有MCH的个体。
    结论:这些结果表明WMH和MCH之间有很强的关联,脑淀粉样血管病和ARIA-H的常见表现这些结果表明,增加的WMH体积可能代表血管淀粉样变性的早期迹象,可能在MCH出现之前。
    BACKGROUND: Increased white matter hyperintensity (WMH) volume visible on MRI is a common finding in Alzheimer\'s disease (AD). We hypothesized that WMH in preclinical AD is associated with the presence of advanced vessel amyloidosis manifested as microhemorrhages (MCH).
    OBJECTIVE: 1) To assess the relationship between baseline WMH volume and baseline MCH. 2) To assess the relationship between longitudinal WMH accumulation and last MRI MCH during the double-blind phase of the A4 trial.
    METHODS: A multicenter, randomized, double-blind, placebo-controlled, Phase 3 study comparing solanezumab with placebo given as infusions once every 4 weeks over 4.5 years in subjects with preclinical AD, defined as having evidence of elevated brain amyloid before the stage of clinically evident cognitive impairment, with an optional open-label extension period.
    METHODS: Anti-Amyloid Treatment in Asymptomatic Alzheimer\'s Disease (A4) study.
    METHODS: A sample of 1157 cognitively unimpaired older adults (mean age = 71.9 years [SD = 4.8 years], 59% women, 59% APOE ε4 carriers).
    METHODS: A linear regression model was used to assess the impact of baseline MCH amount (0, 1, 2+) on WMH volume. A linear mixed-effects model was used to assess the impact of last MRI MCH on longitudinal WMH. All models were corrected for age, sex, grey matter volume, cortical amyloid PET, APOE ε4 status, and treatment group.
    RESULTS: Baseline WMH volume was greater in individuals with more than one MCH compared to those with no MCH (t=4.8, p<0.001). The longitudinal increase in WMH amongst individuals with one (t=2.3, p=0.025) and more than one MCH (t=6.7, p<0.001) at the last MRI was greater than those with no MCH.
    CONCLUSIONS: These results indicate a strong association between WMH and MCH, a common manifestation of cerebral amyloid angiopathy and ARIA-H. These results suggest that increased WMH volume may represent an early sign of vessel amyloidosis, likely prior to the emergence of MCH.
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  • 文章类型: Journal Article
    背景:尽管对创伤性脑损伤(TBI)的神经生物学相关性进行了广泛的研究,对其长期后果的分子决定因素知之甚少,如痴呆和阿尔茨海默病(AD)。
    方法:这里,我们进行了行为研究和广泛的生物分子分析,包括炎症细胞因子,基因表达以及LC-HRMS和MALDI-MS成像的组合,以阐明野生型和APP-SWE小鼠大脑的靶向代谢组学和脂质组学时空改变,AD的遗传模型,在症状前阶段,受到轻度TBI。
    结果:我们发现脑损伤不会影响APP-SWE小鼠的认知能力。然而,我们发现AD的关键标志增加,包括Aβ1-42水平和BACE1表达,在受创伤的转基因小鼠的皮层中。此外,内源性大麻素(eCB)系统的显着变化,或内源性大麻素(eCBome),发生,包括APP-SWE小鼠皮质和海马中内源性大麻素2-AG的水平升高,和N-酰基血清素,第一次在大脑中发现。eCB和eCB样介质生物合成和失活酶的基因表达,以及它们的一些主要分子靶标,也发生了重大变化。我们还确定了大麻素1(CB1)和5-羟色胺能2A(5HT2A)受体之间异聚体的形成,其在APP-SWEmTBI小鼠皮质中的水平增加,可能导致由创伤引起的AD的病理生理学恶化。
    结论:轻度TBI在AD遗传易感小鼠中诱导生化改变,eCBome可能通过与5-羟色胺能系统相互作用在脑损伤和神经退行性疾病之间的发病联系中发挥作用。
    BACKGROUND: Despite extensive studies on the neurobiological correlates of traumatic brain injury (TBI), little is known about its molecular determinants on long-term consequences, such as dementia and Alzheimer\'s disease (AD).
    METHODS: Here, we carried out behavioural studies and an extensive biomolecular analysis, including inflammatory cytokines, gene expression and the combination of LC-HRMS and MALDI-MS Imaging to elucidate the targeted metabolomics and lipidomics spatiotemporal alterations of brains from wild-type and APP-SWE mice, a genetic model of AD, at the presymptomatic stage, subjected to mild TBI.
    RESULTS: We found that brain injury does not affect cognitive performance in APP-SWE mice. However, we detected an increase of key hallmarks of AD, including Aβ1-42 levels and BACE1 expression, in the cortices of traumatized transgenic mice. Moreover, significant changes in the expanded endocannabinoid (eCB) system, or endocannabinoidome (eCBome), occurred, including increased levels of the endocannabinoid 2-AG in APP-SWE mice in both the cortex and hippocampus, and N-acylserotonins, detected for the first time in the brain. The gene expression of enzymes for the biosynthesis and inactivation of eCBs and eCB-like mediators, and some of their main molecular targets, also underwent significant changes. We also identified the formation of heteromers between cannabinoid 1 (CB1) and serotonergic 2A (5HT2A) receptors, whose levels increased in the cortex of APP-SWE mTBI mice, possibly contributing to the exacerbated pathophysiology of AD induced by the trauma.
    CONCLUSIONS: Mild TBI induces biochemical changes in AD genetically predisposed mice and the eCBome may play a role in the pathogenetic link between brain injury and neurodegenerative disorders also by interacting with the serotonergic system.
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  • 文章类型: Journal Article
    这项研究旨在使用自适应光学视网膜成像将对照组和中央凹玻璃疣患者的固定眼球运动(FEM)的细微变化联系起来,以寻找症状前年龄相关性黄斑变性(AMD)的解剖功能标志物。
    我们招募了7个年轻的对照组,4个较旧的控件,和来自Silversiight队列的16例症状性AMD伴中央凹玻璃疣患者。高速研究级自适应光学泛光照明检眼镜(AO-FIO)用于固定眼球运动的单眼视网膜跟踪。该系统允许亚弧分分辨率,以及中央凹区域的高速和无畸变成像。在临床级AO-FIO上使用凝视依赖性成像记录了中心凹玻璃疣的位置和大小。
    FEM以高精度(人眼RMS-S2S=0.0015度)测量,并通过高对比度成像检测到小的中央凹玻璃疣(中值直径=60µm)。微跳幅度,漂移扩散系数,与对照组相比,中央凹玻璃疣患者的ISOline面积(ISOA)明显更大。在玻璃疣参与者中,微扫视幅度与中央凹中心的玻璃疣偏心相关。
    一种新颖的高速高精度视网膜跟踪技术允许在微观水平上表征FEM。凹陷玻璃疣改变了固定稳定性,导致补偿性有限元变化。特别是,小窝水平的玻璃疣似乎对微视幅度和ISOA有更强的影响。小中央凹玻璃疣与固定稳定性之间的意外解剖功能联系为在症状前阶段检测眼部疾病的动眼特征开辟了新的视角。
    UNASSIGNED: This study aims at linking subtle changes of fixational eye movements (FEM) in controls and in patients with foveal drusen using adaptive optics retinal imaging in order to find anatomo-functional markers for pre-symptomatic age-related macular degeneration (AMD).
    UNASSIGNED: We recruited 7 young controls, 4 older controls, and 16 patients with presymptomatic AMD with foveal drusen from the Silversight Cohort. A high-speed research-grade adaptive optics flood illumination ophthalmoscope (AO-FIO) was used for monocular retinal tracking of fixational eye movements. The system allows for sub-arcminute resolution, and high-speed and distortion-free imaging of the foveal area. Foveal drusen position and size were documented using gaze-dependent imaging on a clinical-grade AO-FIO.
    UNASSIGNED: FEM were measured with high precision (RMS-S2S = 0.0015 degrees on human eyes) and small foveal drusen (median diameter = 60 µm) were detected with high contrast imaging. Microsaccade amplitude, drift diffusion coefficient, and ISOline area (ISOA) were significantly larger for patients with foveal drusen compared with controls. Among the drusen participants, microsaccade amplitude was correlated to drusen eccentricity from the center of the fovea.
    UNASSIGNED: A novel high-speed high-precision retinal tracking technique allowed for the characterization of FEM at the microscopic level. Foveal drusen altered fixation stability, resulting in compensatory FEM changes. Particularly, drusen at the foveolar level seemed to have a stronger impact on microsaccade amplitudes and ISOA. The unexpected anatomo-functional link between small foveal drusen and fixation stability opens up a new perspective of detecting oculomotor signatures of eye diseases at the presymptomatic stage.
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  • 文章类型: Journal Article
    背景:多模式生活方式干预可以使整体健康受益,包括认知,在有痴呆症风险的人群中。然而,关于生活方式干预对前驱阿尔茨海默病(AD)患者的影响知之甚少。对该人群的饮食摄入量和对饮食建议的遵守情况知之甚少,因此很难为他们设计量身定制的干预措施。
    方法:一项为期6个月的MIND-ADmini先导随机对照试验(RCT)在瑞典的93名前驱AD参与者中进行,芬兰,德国,和法国。RCT中包括三组:1)多模式生活方式干预(营养指导,锻炼,认知训练,血管/代谢风险管理,和社会刺激);2)多模式生活方式干预+医疗食品;3)定期健康建议(对照组)。通过使用健康饮食指数(HDI)和地中海饮食依从性筛选器(MEDAS),通过简短的食物摄入问卷评估对饮食建议的依从性。使用3天的食物记录对子样本进行了大量和微量营养素的摄入量分析。
    结果:干预组的饮食质量,汇集在一起,在研究结束时,与对照组相比有所改善,用HDI(p=0.026)和MEDAS(p=0.008)测量。与对照组相比,仅生活方式组的MEDAS(p=0.046)显着改善,HDI(p=0.052)几乎显着改善,而在研究期间,生活方式+医疗食物组的HDI(p=0.042)和MEDAS(p=0.007)均有所改善。在随访时,干预组的宏观或微量营养素摄入量没有变化;然而,调整能量摄入后,对照组的几种维生素和矿物质摄入量下降。
    结论:这些结果表明,作为多模式生活方式干预的一部分,饮食干预是可行的,并且可以改善前驱AD患者的饮食质量。干预组的营养摄入量保持不变,而对照组的营养密度降低。
    背景:ClinicalTrials.govNCT03249688,2017-07-08。
    Multimodal lifestyle interventions can benefit overall health, including cognition, in populations at-risk for dementia. However, little is known about the effect of lifestyle interventions in patients with prodromal Alzheimer\'s disease (AD). Even less is known about dietary intake and adherence to dietary recommendations within this population making it difficult to design tailored interventions for them.
    A 6-month MIND-ADmini pilot randomized controlled trial (RCT) was conducted among 93 participants with prodromal AD in Sweden, Finland, Germany, and France. Three arms were included in the RCT: 1) multimodal lifestyle intervention (nutritional guidance, exercise, cognitive training, vascular/metabolic risk management, and social stimulation); 2) multimodal lifestyle intervention + medical food product; and 3) regular health advice (control group). Adherence to dietary advice was assessed with a brief food intake questionnaire by using the Healthy Diet Index (HDI) and Mediterranean Diet Adherence Screener (MEDAS). The intake of macro- and micronutrients were analyzed on a subsample using 3-day food records.
    The dietary quality in the intervention groups, pooled together, improved compared to that of the control group at the end of the study, as measured with by HDI (p = 0.026) and MEDAS (p = 0.008). The lifestyle-only group improved significantly more in MEDAS (p = 0.046) and almost significantly in HDI (p = 0.052) compared to the control group, while the lifestyle + medical food group improved in both HDI (p = 0.042) and MEDAS (p = 0.007) during the study. There were no changes in macro- or micronutrient intake for the intervention groups at follow-up; however, the intakes in the control group declined in several vitamins and minerals when adjusted for energy intake.
    These results suggest that dietary intervention as part of multimodal lifestyle interventions is feasible and results in improved dietary quality in a population with prodromal AD. Nutrient intakes remained unchanged in the intervention groups while the control group showed a decreasing nutrient density.
    ClinicalTrials.gov NCT03249688, 2017-07-08.
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  • 文章类型: Journal Article
    帕金森病(PD)是由其主要运动症状诊断的,这些症状与黑质致密部(SNc)中多巴胺神经元的丢失有关。然而,PD患者在诊断前几年患有各种非运动症状。这些前驱症状被认为与脑干区域如迷走神经背侧运动核(DMV)的路易体病变(LBP)的出现有关。蓝斑(LC)等。这些区域中易受LBP影响的神经元都是缓慢的自主起搏器神经元,由于其Ca2离子的永久流入而表现出升高的氧化应激。毒性α-突触核蛋白(aSyn)的聚集-LBP的主要成分-在长的前驱期间挑战这些脆弱的神经元,大概改变了他们的生物物理学和生理学。与有据可查的晚期帕金森病的病理生理学相反,对前驱PD期间脑干的病理生理学知之甚少。在这次审查中,我们讨论了脑干起搏器神经元中与aSyn聚集相关的离子通道失调及其细胞对它们的反应。虽然毒性aSyn会提高SNc和LC起搏器神经元的氧化应激并加剧其表型,DMV神经元产生一种缓解氧化应激的适应性反应。离子通道失调和细胞适应可能是PD前驱症状的驱动因素。例如,将有毒的aSyn选择性靶向DMV起搏器,提高K+通道的表面密度,这降低了他们的射击速度,导致胃肠道的副交感神经张力降低,这类似于吞咽困难和便秘的前驱PD症状。SNc&LC与DMV起搏器神经元可以解释为什么尽管较早地出现LBP,但后者却比前者长寿。阐明前驱PD的脑干病理生理学可以为生理生物标志物铺平道路,PD的早期诊断和新型神经保护疗法。
    Parkinson\'s disease (PD) is diagnosed by its cardinal motor symptoms that are associated with the loss of dopamine neurons in the substantia nigra pars compacta (SNc). However, PD patients suffer from various non-motor symptoms years before diagnosis. These prodromal symptoms are thought to be associated with the appearance of Lewy body pathologies (LBP) in brainstem regions such as the dorsal motor nucleus of the vagus (DMV), the locus coeruleus (LC) and others. The neurons in these regions that are vulnerable to LBP are all slow autonomous pacemaker neurons that exhibit elevated oxidative stress due to their perpetual influx of Ca2+ ions. Aggregation of toxic α-Synuclein (aSyn) - the main constituent of LBP - during the long prodromal period challenges these vulnerable neurons, presumably altering their biophysics and physiology. In contrast to pathophysiology of late stage parkinsonism which is well-documented, little is known about the pathophysiology of the brainstem during prodromal PD. In this review, we discuss ion channel dysregulation associated with aSyn aggregation in brainstem pacemaker neurons and their cellular responses to them. While toxic aSyn elevates oxidative stress in SNc and LC pacemaker neurons and exacerbates their phenotype, DMV neurons mount an adaptive response that mitigates the oxidative stress. Ion channel dysregulation and cellular adaptations may be the drivers of the prodromal symptoms of PD. For example, selective targeting of toxic aSyn to DMV pacemakers, elevates the surface density of K+ channels, which slows their firing rate, resulting in reduced parasympathetic tone to the gastrointestinal tract, which resembles the prodromal PD symptoms of dysphagia and constipation. The divergent responses of SNc & LC vs. DMV pacemaker neurons may explain why the latter outlive the former despite presenting LBPs earlier. Elucidation the brainstem pathophysiology of prodromal PD could pave the way for physiological biomarkers, earlier diagnosis and novel neuroprotective therapies for PD.
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