Departments of Child & Adolescent Psychiatry, Neuroscience & Physiology, and Psychiatry, and the Neuroscience Institute, New York University Langone Health, New York, New York, USA.
Center for Dementia Research, The Nathan Kline Institute for Psychiatric Research, New York State Office of Mental Health, Orangeburg, New York, USA.
Epilepsia. 2023 Jan;64(1):231-246. doi: 10.1111/epi.17462. Epub 2022 Nov 29.
To test the hypothesis that high-frequency oscillations (HFOs) between 250 and 500 Hz occur in mouse models of Alzheimer's disease (AD) and thus are not unique to epilepsy.
Experiments were conducted in three mouse models of AD: Tg2576 mice that simulate a form of familial AD, presenilin 2 knock-out (PS2KO) mice, and the Ts65Dn model of Down's syndrome. We recorded HFOs using wideband (0.1-500 Hz, 2 kHz) intra-hippocampal and cortical surface electroencephalography (EEG) at 1 month until 24 months of age during wakefulness, slow wave sleep (SWS), and rapid eye movement (REM) sleep. In addition, interictal spikes (IISs) and seizures were analyzed for the possible presence of HFOs. Comparisons were made to the intra-hippocampal kainic acid and pilocarpine models of epilepsy.
We describe for the first time that hippocampal and cortical HFOs are a new EEG abnormality in AD mouse models. HFOs occurred in all transgenic mice but no controls. They were also detectable as early as 1 month of age and prior to amyloid beta plaque neuropathology. HFOs were most frequent during SWS (vs REM sleep or wakefulness). Notably, HFOs in the AD and epilepsy models were indistinguishable in both spectral frequency and duration. HFOs also occurred during IISs and seizures in the AD models, although with altered spectral properties compared to isolated HFOs.
Our data demonstrate that HFOs, an epilepsy biomarker with high translational value, are not unique to epilepsy and thus not disease specific. Our findings also strengthen the idea of hyperexcitability in AD and its significant overlap with epilepsy. HFOs in AD mouse models may serve as an EEG biomarker, which is detectable from the scalp and thus amenable to noninvasive detection in people at risk for AD.
验证假说，即高频振荡（HFOs）在 250 至 500Hz 之间出现在阿尔茨海默病（AD）的小鼠模型中，因此并非癫痫所特有。
在三种 AD 小鼠模型中进行了实验：模拟家族性 AD 的 Tg2576 小鼠、早老素 2 敲除（PS2KO）小鼠和唐氏综合征的 Ts65Dn 模型。我们在清醒、慢波睡眠（SWS）和快速眼动（REM）睡眠期间，使用脑内（0.1-500Hz，2kHz）的宽带和脑表面脑电图（EEG）记录 HFOs，记录时间从 1 个月到 24 个月。此外，还分析了发作间期棘波（IISs）和癫痫发作中 HFOs 的存在。并将其与脑内海人酸和匹鲁卡品癫痫模型进行了比较。
我们首次描述了 HFOs 是 AD 小鼠模型中的一种新的 EEG 异常。在所有转基因小鼠中都发现了 HFOs，但在对照组中没有。HFOs 在 1 个月大时就可以检测到，并且早于淀粉样β斑块神经病理学。HFOs 在 SWS 期间最为频繁（与 REM 睡眠或清醒状态相比）。值得注意的是，AD 和癫痫模型中的 HFOs 在频谱频率和持续时间上是无法区分的。在 AD 模型中，HFOs 也发生在 IISs 和癫痫发作期间，但与孤立的 HFOs 相比，其频谱特性发生了改变。
我们的数据表明，HFOs 是一种具有高转化价值的癫痫生物标志物，并非癫痫所特有，因此也不是疾病特异性的。我们的研究结果也进一步证实了 AD 中的过度兴奋及其与癫痫的显著重叠。AD 小鼠模型中的 HFOs 可能作为一种 EEG 生物标志物，可从头皮上检测到，因此可用于 AD 高危人群的非侵入性检测。
