Research into hippocampal self-regulation abilities may help determine the clinical significance of hippocampal hyperactivity throughout the pathophysiological continuum of Alzheimer's disease. In this study, we aimed to identify the effects of amyloid-β peptide 42 (amyloid-β42) and phosphorylated tau on the patterns of functional connectomics involved in hippocampal downregulation. We identified 48 cognitively unimpaired participants (22 with elevated CSF amyloid-β peptide 42 levels, 15 with elevated CSF phosphorylated tau levels, mean age of 62.705 ± 4.628 years), from the population-based 'Alzheimer's and Families' study, with baseline MRI, CSF biomarkers, APOE genotyping and neuropsychological evaluation. We developed a closed-loop, real-time functional MRI neurofeedback task with virtual reality and tailored it for training downregulation of hippocampal subfield cornu ammonis 1 (CA1). Neurofeedback performance score, cognitive reserve score, hippocampal volume, number of apolipoprotein ε4 alleles and sex were controlled for as confounds in all cross-sectional analyses. First, using voxel-wise multiple regression analysis and controlling for CSF biomarkers, we identified the effect of healthy ageing on eigenvector centrality, a measure of each voxel's overall influence based on iterative whole-brain connectomics, during hippocampal CA1 downregulation. Then, controlling for age, we identified the effects of abnormal CSF amyloid-β42 and phosphorylated tau levels on eigenvector centrality during hippocampal CA1 downregulation. Across subjects, our main findings during hippocampal downregulation were: (i) in the absence of abnormal biomarkers, age correlated with eigenvector centrality negatively in the insula and midcingulate cortex, and positively in the inferior temporal gyrus; (ii) abnormal CSF amyloid-β42 (<1098) correlated negatively with eigenvector centrality in the anterior cingulate cortex and primary motor cortex; and (iii) abnormal CSF phosphorylated tau levels (>19.2) correlated with eigenvector centrality positively in the ventral striatum, anterior cingulate and somatosensory cortex, and negatively in the precuneus and orbitofrontal cortex. During resting state functional MRI, similar eigenvector centrality patterns in the cingulate had previously been associated to CSF biomarkers in mild cognitive impairment and dementia patients. Using the developed closed-loop paradigm, we observed such patterns, which are characteristic of advanced disease stages, during a much earlier presymptomatic phase. In the absence of CSF biomarkers, our non-invasive, interactive, adaptive and gamified neuroimaging procedure may provide important information for clinical prognosis and monitoring of therapeutic efficacy. We have released the developed paradigm and analysis pipeline as open-source software to facilitate replication studies.

中文翻译：

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最早的淀粉样蛋白和tau沉积物在闭环海马下调期间调节边缘网络的影响。

对海马自我调节能力的研究可能有助于确定阿尔茨海默氏病整个病理生理连续过程中海马过度活跃的临床意义。在这项研究中，我们旨在确定淀粉样蛋白β肽42（淀粉样蛋白β42）和磷酸化的tau对参与海马下调的功能性连接组学模式的影响。我们通过基于基线MRI的基于人群的“阿尔茨海默氏症和家庭”研究确定了48名无认知障碍的参与者（22名CSF淀粉样β肽水平升高，15名CSF磷酸化tau水平升高，平均年龄为62.705±4.628岁） ，CSF生物标志物，APOE基因分型和神经心理学评估。我们开发了一个闭环 具有虚拟现实的实时功能性MRI神经反馈任务，并将其定制为训练海马亚视野角膜氨氮1（CA1）的下调。在所有横断面分析中，均以神经反馈表现评分，认知储备评分，海马体积，载脂蛋白ε4等位基因数量和性别作为控制因素。首先，使用体素多元回归分析并控制CSF生物标记物，我们确定了健康衰老对本征中心性的影响，该特性是在海马CA1下调过程中基于迭代全脑连接学对每个体素整体影响的一种度量。然后，控制年龄，我们确定了海马CA1下调过程中异常CSF淀粉样蛋白β42和磷酸化tau水平对本征向量中心的影响。跨学科 我们在海马下调过程中的主要发现是：（i）在没有异常生物标志物的情况下，年龄与岛突和中齿皮层的特征向量中心负相关，在颞下回正相关；（ii）CSF淀粉样蛋白β42异常（<1098）与前扣带回皮层和原发性运动皮层的特征向量中心性呈负相关；（iii）脑脊液磷酸化tau水平异常（> 19.2）与本征中心在腹侧纹状体，前扣带回和体感皮层中呈正相关，而在前额皮层和眶额皮层中呈负相关。在静息状态下的功能性MRI期间，轻度认知障碍和痴呆症患者的扣带状特征向量集中度模式以前曾与CSF生物标志物相关。使用发达的闭环范式，我们在更早的症状前阶段观察到了这种模式，这些模式是疾病晚期的特征。在没有脑脊液生物标志物的情况下，我们的非侵入性，交互式，适应性和游戏化的神经影像学检查程序可能为临床预后和监测疗效提供重要信息。我们已经发布了开发的范例和分析管道作为开源软件，以促进复制研究。