Connectome Signatures of Hyperexcitation in Cognitively Intact Middle-Aged Female APOE-ε4 Carriers
Connectome Signatures of Hyperexcitation in Cognitively Intact Middle-Aged Female APOE-ε4 Carriers
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DOI：
10.1093/cercor/bhaa190
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发表时间：
2020-12-01
期刊：
影响因子：
3.7
通讯作者：
Leow, Alex
中科院分区：
文献类型：
--
作者：
Fortel, Igor;Korthauer, Laura E.;Leow, Alex
突触功能障碍被认为是阿尔茨海默病中最早的大脑变化之一，导致神经元回路“过度兴奋”。在这项研究中，我们使用混合静息状态结构连接组来评估每个大脑区域的新型超兴奋指标（HI），以探测认知完整的中年载脂蛋白E (APOE) epsilon 4携带者和非携带者（每组16名男性/22名女性）连接组水平的兴奋-抑制平衡。通过三种相互作用（性别、年龄和APOE-epsilon 4携带者状态）的回归来评估APOE-epsilon 4对男女之间兴奋-抑制平衡的影响，并跨越40-60岁的年龄范围，结果显示，与非携带者（从50岁开始）相比，女性携带者的HI明显升高。过度兴奋在男性组中不明显。此外，在女性携带者中，过度兴奋程度与三个区域的工作记忆表现（通过虚拟莫里斯水任务评估）呈显著正相关：左侧三角部、左侧海马和左侧扣带回峡部。记忆相关回路的兴奋增加可能是神经元资源为记忆集中活动补偿性招募的证据。总之，我们的结果与已知的阿尔茨海默病的性别差异是一致的；女性APOE-epsilon 4携带者在全球范围内破坏了兴奋-抑制平衡，这可能导致更大的神经病理学疾病易感性。
Synaptic dysfunction is hypothesized to be one of the earliest brain changes in Alzheimer's disease, leading to "hyperexcitability" in neuronal circuits. In this study, we evaluated a novel hyperexcitation indicator (HI) for each brain region using a hybrid resting-state structural connectome to probe connectome-level excitation-inhibition balance in cognitively intact middle-aged apolipoprotein E (APOE) epsilon 4 carriers with noncarriers (16 male/22 female in each group). Regression with three-way interactions (sex, age, and APOE-epsilon 4 carrier status) to assess the effect of APOE-epsilon 4 on excitation-inhibition balance within each sex and across an age range of 40-60 years yielded a significant shift toward higher HI in female carriers compared with noncarriers (beginning at 50 years). Hyperexcitation was insignificant in the male group. Further, in female carriers the degree of hyperexcitation exhibited significant positive correlation with working memory performance (evaluated via a virtual Morris Water task) in three regions: the left pars triangularis, left hippocampus, and left isthmus of cingulate gyrus. Increased excitation of memory-related circuits may be evidence of compensatory recruitment of neuronal resources for memory-focused activities. In sum, our results are consistent with known Alzheimer's disease sex differences; in that female APOE-epsilon 4 carriers have globally disrupted excitation-inhibition balance that may confer greater vulnerability to disease neuropathology.