Tu Jiaxin Cindy, Millar Peter R, Strain Jeremy F, Eck Andrew, Adeyemo Babatunde, Snyder Abraham Z, Daniels Alisha, Karch Celeste, Huey Edward D, McDade Eric, Day Gregory S, Yakushev Igor, Hassenstab Jason, Morris John, Llibre-Guerra Jorge J, Ibanez Laura, Jucker Mathias, Mendez Patricio Chrem, Perrin Richard J, Benzinger Tammie L S, Jack Clifford R, Betzel Richard, Ances Beau M, Eggebrecht Adam T, Gordon Brian A, Wheelock Muriah D
Department of Radiology, Washington University in St. Louis, St. Louis, MO, USA.
Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA.
Netw Neurosci. 2024 Dec 10;8(4):1265-1290. doi: 10.1162/netn_a_00395. eCollection 2024.
Hub regions in the brain, recognized for their roles in ensuring efficient information transfer, are vulnerable to pathological alterations in neurodegenerative conditions, including Alzheimer's disease (AD). Computational simulations and animal experiments have hinted at the theory of activity-dependent degeneration as the cause of this hub vulnerability. However, two critical issues remain unresolved. First, past research has not clearly distinguished between two scenarios: hub regions facing a higher risk of connectivity disruption (targeted attack) and all regions having an equal risk (random attack). Second, human studies offering support for activity-dependent explanations remain scarce. We refined the hub disruption index to demonstrate a hub disruption pattern in functional connectivity in autosomal dominant AD that aligned with targeted attacks. This hub disruption is detectable even in preclinical stages, 12 years before the expected symptom onset and is amplified alongside symptomatic progression. Moreover, hub disruption was primarily tied to regional differences in global connectivity and sequentially followed changes observed in amyloid-beta positron emission tomography cortical markers, consistent with the activity-dependent degeneration explanation. Taken together, our findings deepen the understanding of brain network organization in neurodegenerative diseases and could be instrumental in refining diagnostic and targeted therapeutic strategies for AD in the future.
大脑中的枢纽区域因在确保高效信息传递方面的作用而闻名，在包括阿尔茨海默病（AD）在内的神经退行性疾病中，这些区域易受病理改变的影响。计算模拟和动物实验暗示了活动依赖性退化理论是导致这种枢纽易损性的原因。然而，有两个关键问题仍未得到解决。首先，过去的研究没有明确区分两种情况：枢纽区域面临更高的连接中断风险（靶向攻击）和所有区域具有同等风险（随机攻击）。其次，支持活动依赖性解释的人体研究仍然很少。我们改进了枢纽破坏指数，以证明常染色体显性AD功能连接中的枢纽破坏模式与靶向攻击一致。这种枢纽破坏即使在临床前阶段，即在预期症状出现前12年就可以检测到，并且随着症状进展而加剧。此外，枢纽破坏主要与全局连接性的区域差异相关，并依次跟随在淀粉样β正电子发射断层扫描皮质标记物中观察到的变化，这与活动依赖性退化解释一致。综上所述，我们的研究结果加深了对神经退行性疾病中脑网络组织的理解，并可能有助于未来完善AD的诊断和靶向治疗策略。
