Alzheimer’s disease neurodegeneration is thought to spread across anatomically and functionally connected brain regions. However, the precise sequence of spread remains ambiguous. The prevailing model used to guide in vivo human neuroimaging and non-human animal research assumes that Alzheimer’s degeneration starts in the entorhinal cortices, before spreading to the temporoparietal cortex. Challenging this model, we previously provided evidence that in vivo markers of neurodegeneration within the nucleus basalis of Meynert (NbM), a subregion of the basal forebrain heavily populated by cortically projecting cholinergic neurons, precedes and predicts entorhinal degeneration. There have been few systematic attempts at directly comparing staging models using in vivo longitudinal biomarker data, and none to our knowledge testing if comparative evidence generalizes across independent samples. Here we addressed the sequence of pathological staging in Alzheimer’s disease using two independent samples of the Alzheimer’s Disease Neuroimaging Initiative (n1 = 284; n2 = 553) with harmonized CSF assays of amyloid-β and hyperphosphorylated tau (pTau), and longitudinal structural MRI data over 2 years. We derived measures of grey matter degeneration in a priori NbM and the entorhinal cortical regions of interest. To examine the spreading of degeneration, we used a predictive modelling strategy that tests whether baseline grey matter volume in a seed region accounts for longitudinal change in a target region. We demonstrated that predictive spread favoured the NbM→entorhinal over the entorhinal→NbM model. This evidence generalized across the independent samples. We also showed that CSF concentrations of pTau/amyloid-β moderated the observed predictive relationship, consistent with evidence in rodent models of an underlying trans-synaptic mechanism of pathophysiological spread. The moderating effect of CSF was robust to additional factors, including clinical diagnosis. We then applied our predictive modelling strategy to an exploratory whole-brain voxel-wise analysis to examine the spatial specificity of the NbM→entorhinal model. We found that smaller baseline NbM volumes predicted greater degeneration in localized regions of the entorhinal and perirhinal cortices. By contrast, smaller baseline entorhinal volumes predicted degeneration in the medial temporal cortex, recapitulating a prior influential staging model. Our findings suggest that degeneration of the basal forebrain cholinergic projection system is a robust and reliable upstream event of entorhinal and neocortical degeneration, calling into question a prevailing view of Alzheimer’s disease pathogenesis.

中文翻译：

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基底前脑体积可靠地预测阿尔茨海默病的皮质扩散。

阿尔茨海默病神经退行性变被认为会扩散到解剖学和功能连接的大脑区域。然而，确切的传播顺序仍然模棱两可。用于指导体内人类神经成像和非人类动物研究的流行模型假设阿尔茨海默病的退化始于内嗅皮质，然后扩散到颞顶叶皮质。挑战这个模型，我们之前提供的证据表明，Meynert 基底核 (NbM) 的体内神经变性标志物是由皮质突出的胆碱能神经元大量分布的基底前脑子区域，先于并预测内嗅变性。使用体内直接比较分期模型的系统尝试很少纵向生物标志物数据，如果比较证据在独立样本中推广，我们的知识测试没有。在这里，我们使用阿尔茨海默病神经影像学计划 ( n1 = 284; n2 = 553) 的两个独立样本以及淀粉样蛋白-β 和过度磷酸化 tau (pTau) 的协调脑脊液测定以及纵向结构 MRI 数据来解决阿尔茨海默病的病理分期序列2年以上。我们先验地得出灰质退化的测量值NbM 和感兴趣的内嗅皮层区域。为了检查退化的传播，我们使用了一种预测建模策略来测试种子区域中的基线灰质体积是否解释了目标区域的纵向变化。我们证明了预测传播有利于 NbM→entorhinal 而不是 entorhinal→NbM 模型。这一证据在独立样本中得到推广。我们还表明，脑脊液中 pTau/淀粉样蛋白-β 的浓度缓和了观察到的预测关系，这与啮齿动物模型中潜在的病理生理学传播的跨突触机制的证据一致。脑脊液的调节作用对包括临床诊断在内的其他因素是稳健的。然后，我们将我们的预测建模策略应用于探索性全脑体素分析，以检查 NbM→entorhinal 模型的空间特异性。我们发现较小的基线 NbM 体积预示着内嗅皮质和 perirhinal 皮质局部区域的退化程度更大。相比之下，较小的基线内嗅体积预测内侧颞叶皮层的退化，概括了先前有影响的分期模型。我们的研究结果表明，基底前脑胆碱能投射系统的退化是内嗅和新皮质退化的一个强大而可靠的上游事件，这对阿尔茨海默病发病机制的普遍观点提出了质疑。我们发现较小的基线 NbM 体积预示着内嗅皮质和 perirhinal 皮质局部区域的退化程度更大。相比之下，较小的基线内嗅体积预测内侧颞叶皮层的退化，概括了先前有影响的分期模型。我们的研究结果表明，基底前脑胆碱能投射系统的退化是内嗅和新皮质退化的一个强大而可靠的上游事件，这对阿尔茨海默病发病机制的普遍观点提出了质疑。我们发现较小的基线 NbM 体积预示着内嗅皮质和 perirhinal 皮质局部区域的退化程度更大。相比之下，较小的基线内嗅体积预测内侧颞叶皮层的退化，概括了先前有影响的分期模型。我们的研究结果表明，基底前脑胆碱能投射系统的退化是内嗅和新皮质退化的一个强大而可靠的上游事件，这对阿尔茨海默病发病机制的普遍观点提出了质疑。