Department of Neurology, University of Virginia School of Medicine, Charlottesville, Virginia, US.
Department of Neuroscience, University of Virginia, Charlottesville, Virginia, US.
Alzheimers Dement. 2023 Jun;19(6):2697-2706. doi: 10.1002/alz.12943. Epub 2023 Jan 17.
Alzheimer's disease (AD) patients have a high risk of developing mesial temporal lobe epilepsy (MTLE) and subclinical epileptiform activity. MTLE in AD worsens outcomes. Therefore, we need to understand the overlap between these disease processes. We hypothesize that AD with MTLE represents a distinct subtype of AD, with the interplay between tau and epileptiform activity at its core. We discuss shared pathological features including histopathology, an initial mesial temporal lobe (MTL) hyperexcitability followed by MTL dysfunction and involvement of same networks in memory (AD) and seizures (MTLE). We provide evidence that tau accumulation linearly increases neuronal hyperexcitability, neuronal hyper-excitability increases tau secretion, tau can provoke seizures, and tau reduction protects against seizures. We speculate that AD genetic mutations increase tau, which causes proportionate neuronal loss and/or hyperexcitability, leading to seizures. We discuss that tau burden in MTLE predicts cognitive deficits among (1) AD and (2) MTLE without AD. Finally, we explore the possibility that anti-seizure medications improve cognition by reducing neuronal hyper-excitability, which reduces seizures and tau accumulation and spread. HIGHLIGHTS: We hypothesize that patients with Alzheimer's disease (AD) and mesial temporal lobe epilepsy (MTLE) represents a distinct subtype of AD. AD and MTLE share histopathological features and involve overlapping neuronal and cortical networks. Hyper-phosphorylated tau (pTau) increases neuronal excitability and provoke seizures, neuronal excitability increases pTau, and pTau reduction reduces neuronal excitability and protects against seizures. The pTau burden in MTL predicts cognitive deficits among (1) AD and (2) MTLE without AD. We speculate that anti-seizure medications improve cognition by reducing neuronal excitability, which reduces seizures and pTau.
阿尔茨海默病（AD）患者发生内侧颞叶癫痫（MTLE）和亚临床痫样活动的风险较高。AD 合并 MTLE 会使结局恶化。因此，我们需要了解这些疾病过程之间的重叠。我们假设 AD 合并 MTLE 代表了 AD 的一个独特亚型，其核心是 tau 与痫样活动的相互作用。我们讨论了包括组织病理学在内的共同病理特征，即初始内侧颞叶（MTL）兴奋性增高，随后 MTL 功能障碍以及相同的网络参与记忆（AD）和癫痫发作（MTLE）。有证据表明 tau 聚集会使神经元兴奋性线性增加，神经元兴奋性增加会促使 tau 分泌，tau 可以引发癫痫发作，tau 减少可预防癫痫发作。我们推测 AD 遗传突变会增加 tau，导致神经元不成比例地丢失和/或过度兴奋，从而引发癫痫发作。我们讨论了 MTLE 中的 tau 负担可预测（1）AD 和（2）无 AD 的 MTLE 患者的认知缺陷。最后，我们探讨了抗癫痫药物通过减少神经元过度兴奋来改善认知的可能性，这种作用可减少癫痫发作和 tau 的积累和扩散。要点：我们假设阿尔茨海默病（AD）和内侧颞叶癫痫（MTLE）患者代表了 AD 的一个独特亚型。AD 和 MTLE 具有共同的组织病理学特征，并涉及重叠的神经元和皮质网络。过度磷酸化的 tau（pTau）增加神经元兴奋性并引发癫痫发作，神经元兴奋性增加 pTau，pTau 减少则降低神经元兴奋性并预防癫痫发作。MTL 中的 pTau 负担可预测（1）AD 和（2）无 AD 的 MTLE 患者的认知缺陷。我们推测抗癫痫药物通过降低神经元兴奋性来改善认知，从而减少癫痫发作和 pTau。
