Malpas Charles B, Saling Michael M, Velakoulis Dennis, Desmond Patricia, O'Brien Terence J
Melbourne Brain Centre, Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Victoria, Australia.
Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, Australia.
J Alzheimers Dis. 2015;47(4):965-75. doi: 10.3233/JAD-142643.
Alzheimer's disease (AD) is characterized by two primary pathologies: tau-related neurofibrillary tangles and the extracellular accumulation of amyloid-β (Aβ). The development of these pathologies is topologically distinct early in the disease, with Aβ beginning to accumulate as a diffuse, neocortical pathology, while tau-related pathology begins to form in mesial temporal regions. This study investigated the hypothesis that, by virtue of this distinction, there exist preferential associations between the primary pathologies and aspects of the cognitive phenotype. We investigated the relationship between cerebrospinal fluid (CSF) biomarkers for tau and Aβ pathologies with neurocognitive measures in 191 patients with mild cognitive impairment (MCI). Participants completed cognitive tests of new learning, information processing speed, and working memory. Separate regression models were computed and then followed up with mediation analyses to examine the predictive status of CSF biomarkers. The effect of Aβ on learning was mediated by phospho-tau (p = 0.008). In contrast, Aβ had a direct effect on information processing speed that was not mediated by phospho-tau (p = 0.59). No predictors were significant for working memory. This study provided evidence for a differential relationship of Aβ and phospho-tau pathologies on the neurocognitive phenotype of MCI. This supports the proposition that these primary AD pathologies maximally affect different aspects of cognition, and has potential implications for cognitive assessments and the use of biomarkers in disease-modifyingtherapeutic trials.
阿尔茨海默病（AD）的特征在于两种主要病变：与tau相关的神经原纤维缠结和淀粉样蛋白β（Aβ）的细胞外积聚。这些病变在疾病早期的发展在拓扑结构上是不同的，Aβ开始作为一种弥漫性的新皮质病变积聚，而与tau相关的病变则开始在颞叶内侧区域形成。本研究调查了这样一种假说，即由于这种差异，主要病变与认知表型的各个方面之间存在优先关联。我们在191名轻度认知障碍（MCI）患者中研究了脑脊液（CSF）中tau和Aβ病变生物标志物与神经认知指标之间的关系。参与者完成了新学习、信息处理速度和工作记忆的认知测试。计算了单独的回归模型，然后进行中介分析以检验CSF生物标志物的预测状态。Aβ对学习的影响由磷酸化tau介导（p = 0.008）。相比之下，Aβ对信息处理速度有直接影响，且不受磷酸化tau介导（p = 0.59）。没有预测指标对工作记忆有显著影响。本研究为Aβ和磷酸化tau病变在MCI神经认知表型上的差异关系提供了证据。这支持了这些主要的AD病变对认知的不同方面产生最大影响这一观点，并对认知评估以及疾病修饰治疗试验中生物标志物的使用具有潜在意义。
