Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Feodor-Lynen Straße 17, 81377 Munich, Germany.
German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
Brain. 2018 Apr 1;141(4):1186-1200. doi: 10.1093/brain/awy008.
Patients with Alzheimer's disease vary in their ability to sustain cognitive abilities in the presence of brain pathology. A major open question is which brain mechanisms may support higher reserve capacity, i.e. relatively high cognitive performance at a given level of Alzheimer's pathology. Higher functional MRI-assessed functional connectivity of a hub in the left frontal cortex is a core candidate brain mechanism underlying reserve as it is associated with education (i.e. a protective factor often associated with higher reserve) and attenuated cognitive impairment in prodromal Alzheimer's disease. However, no study has yet assessed whether such hub connectivity of the left frontal cortex supports reserve throughout the evolution of pathological brain changes in Alzheimer's disease, including the presymptomatic stage when cognitive decline is subtle. To address this research gap, we obtained cross-sectional resting state functional MRI in 74 participants with autosomal dominant Alzheimer's disease, 55 controls from the Dominantly Inherited Alzheimer's Network and 75 amyloid-positive elderly participants, as well as 41 amyloid-negative cognitively normal elderly subjects from the German Center of Neurodegenerative Diseases multicentre study on biomarkers in sporadic Alzheimer's disease. For each participant, global left frontal cortex connectivity was computed as the average resting state functional connectivity between the left frontal cortex (seed) and each voxel in the grey matter. As a marker of disease stage, we applied estimated years from symptom onset in autosomal dominantly inherited Alzheimer's disease and cerebrospinal fluid tau levels in sporadic Alzheimer's disease cases. In both autosomal dominant and sporadic Alzheimer's disease patients, higher levels of left frontal cortex connectivity were correlated with greater education. For autosomal dominant Alzheimer's disease, a significant left frontal cortex connectivity × estimated years of onset interaction was found, indicating slower decline of memory and global cognition at higher levels of connectivity. Similarly, in sporadic amyloid-positive elderly subjects, the effect of tau on cognition was attenuated at higher levels of left frontal cortex connectivity. Polynomial regression analysis showed that the trajectory of cognitive decline was shifted towards a later stage of Alzheimer's disease in patients with higher levels of left frontal cortex connectivity. Together, our findings suggest that higher resilience against the development of cognitive impairment throughout the early stages of Alzheimer's disease is at least partially attributable to higher left frontal cortex-hub connectivity.
阿尔茨海默病患者的大脑病理存在差异，其认知能力的维持能力也存在差异。一个主要的悬而未决的问题是，哪些大脑机制可能支持更高的储备能力，即给定阿尔茨海默病病理水平下相对较高的认知表现。左额皮质中一个枢纽的功能磁共振评估的功能连接较高，是储备能力的核心候选大脑机制，因为它与教育有关（即与更高储备能力相关的保护因素），并且可以减轻前驱期阿尔茨海默病的认知障碍。然而，尚无研究评估左额皮质的这种枢纽连接是否在阿尔茨海默病的病理脑变化的整个演变过程中支持储备，包括认知能力下降细微的无症状阶段。为了解决这一研究空白，我们在 74 名常染色体显性阿尔茨海默病患者、55 名来自常染色体显性阿尔茨海默病网络的对照组和 75 名淀粉样蛋白阳性的老年参与者以及 41 名淀粉样蛋白阴性的认知正常的老年参与者中获得了横断面静息状态功能磁共振成像。对于每个参与者，全局左额皮质连接性作为左额皮质（种子）与灰质中每个体素之间的静息状态功能连接性的平均值来计算。作为疾病阶段的标志物，我们应用常染色体显性遗传性阿尔茨海默病的症状发作估计年限和散发性阿尔茨海默病病例的脑脊液 tau 水平。在常染色体显性和散发性阿尔茨海默病患者中，左额皮质连接性越高，与受教育程度越高相关。对于常染色体显性遗传性阿尔茨海默病，发现左额皮质连接性×估计发病年限的显著交互作用，表明在连接性较高的情况下，记忆和整体认知能力的下降速度较慢。同样，在散发性淀粉样蛋白阳性的老年受试者中，tau 对认知的影响在左额皮质连接性较高时减弱。多项式回归分析表明，在左额皮质连接性较高的患者中，认知衰退的轨迹向阿尔茨海默病的晚期阶段转移。总之，我们的发现表明，在阿尔茨海默病的早期阶段，认知障碍发展的恢复力较高至少部分归因于左额皮质中枢连接性较高。
