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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基础前脑体积可靠地预测阿尔茨海默病的皮质扩散。


阿尔茨海默病神经变性被认为会扩散到解剖学和功能上相连的大脑区域。然而，传播的确切顺序仍然不明确。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氏症的变性始于内嗅皮质，然后扩散到颞顶皮质。为了挑战这一模型，我们之前提供的证据表明，Meynert 基底核 (NbM) 内的神经变性标记物（NbM 是基底前脑的一个亚区域，大量分布着皮质投射胆碱能神经元）先于并预测内嗅变性。很少有系统性的尝试使用体内纵向生物标志物数据直接比较分期模型，并且据我们所知，没有测试比较证据是否适用于独立样本。在这里，我们使用阿尔茨海默病神经影像计划的两个独立样本（ n1 = 284； n2 = 553）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顺序超过2年。我们得出了先验NbM 和内嗅皮质感兴趣区域中灰质变性的测量结果。为了检查退化的扩散，我们使用了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，预测传播有利于 NbM→内嗅模型，而不是内嗅→NbM 模型。该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 的浓度调节了观察到的预测关系，这与啮齿动物模型中病理生理学传播的潜在跨突触机制的证据一致。脑脊液的调节作用对于其他因素（包括临床诊断）来说是稳健的。然后，我们将预测建模策略应用于探索性全脑体素分析，以检查 NbM→内嗅模型的空间特异性。我们发现，较小的基线 NbM 体积预示着内嗅和周围皮质局部区域的更大退化。相比之下，较小的基线内嗅体积预示着内侧颞叶皮层的退化，概括了之前有影响力的分期模型。我们的研究结果表明，基底前脑胆碱能投射系统的变性是内嗅和新皮质变性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。