Lam Alice D, Thibault Emma G, Mayblyum Danielle V, Hsieh Stephanie, Pellerin Kyle R, Sternberg Eliezer J, Viswanathan Anand, Buss Stephanie, Sarkis Rani A, Jacobs Heidi I L, Johnson Keith A, Sperling Reisa A
From the Department of Neurology (A.D.L., S.H., K.R.P., A.V., K.A.J.), Massachusetts General Hospital, Boston; Harvard Medical School (A.D.L., A.V., S.B., R.A. Sarkis, H.L.J., K.A.J., R.A. Sperling), Boston; Department of Radiology (E.G.T., D.V.M., H.L.J., K.A.J.), Massachusetts General Hospital, Boston; Department of Neurology (E.J.S.), Milford Regional Medical Center; Department of Neurology (S.B.), Beth Israel Deaconess Medical Center, Boston; and Department of Neurology (R.A.Sarkis, R.A.Sperling), Brigham and Women's Hospital, Boston, MA.
Neurology. 2024 Nov 12;103(9):e209920. doi: 10.1212/WNL.0000000000209920. Epub 2024 Sep 27.
Alzheimer disease (AD) is associated with a 2 to 3-fold increased risk of developing late-onset focal epilepsy, yet it remains unclear how development of focal epilepsy in AD is related to AD pathology. The objective of this study was to examine spatial relationships between the epileptogenic zone and tau deposition, amyloid deposition, and brain atrophy in individuals with AD who developed late-onset, otherwise unexplained focal epilepsy. We hypothesized that if network hyperexcitability is mechanistically linked to AD pathology, then there would be increased tau and amyloid deposition within the epileptogenic hemisphere.
In this cross-sectional study, we performed tau and amyloid PET imaging, brain MRI, and overnight scalp EEG in individuals with early clinical stages of AD who developed late-onset, otherwise unexplained focal epilepsy (AD-Ep). Participants were referred from epilepsy and memory disorders clinics at our institutions. We determined epilepsy localization based on EEG findings and seizure semiology. We quantified tau deposition, amyloid deposition, and atrophy across brain regions and calculated asymmetry indices for these measures. We compared findings in AD-Ep with those in a control AD group without epilepsy (AD-NoEp).
The AD-Ep group included 8 individuals with a mean age of 69.5 ± 4.2 years at PET imaging. The AD-NoEp group included 14 individuals with a mean age of 71.7 ± 9.8 years at PET imaging. In AD-Ep, we found a highly asymmetric pattern of tau deposition, with significantly greater tau in the epileptogenic hemisphere. Amyloid deposition and cortical atrophy were also greater in the epileptogenic hemisphere, although the magnitudes of asymmetry were reduced compared with tau. Compared with AD-NoEp, the AD-Ep group had significantly greater tau asymmetry and trends toward greater asymmetry of amyloid and atrophy. AD-Ep also had significantly greater amyloid burden bilaterally and trends toward greater tau burden within the epileptogenic hemisphere, compared with AD-NoEp.
Our results reveal a spatial association between the epileptogenic focus and tau deposition, amyloid deposition, and neurodegeneration in early clinical stages of AD. Within the limitations of a cross-sectional study with small sample sizes, these findings contribute to our understanding of the clinicopathologic heterogeneity of AD, demonstrating an association between focal epilepsy and lateralized pathology in AD.
阿尔茨海默病（AD）与晚发性局灶性癫痫的发病风险增加2至3倍相关，但AD中局灶性癫痫的发生与AD病理学之间的关系仍不清楚。本研究的目的是检查晚发性、原因不明的局灶性癫痫的AD患者中致痫区与tau蛋白沉积、淀粉样蛋白沉积和脑萎缩之间的空间关系。我们假设，如果网络兴奋性过高与AD病理学存在机制上的联系，那么致痫半球内的tau蛋白和淀粉样蛋白沉积将会增加。
在这项横断面研究中，我们对处于AD临床早期且发生晚发性、原因不明的局灶性癫痫（AD-Ep）的个体进行了tau蛋白和淀粉样蛋白PET成像、脑MRI以及夜间头皮脑电图检查。参与者来自我们机构的癫痫和记忆障碍诊所。我们根据脑电图结果和癫痫发作症状学确定癫痫定位。我们对全脑区域的tau蛋白沉积、淀粉样蛋白沉积和萎缩进行了量化，并计算了这些指标的不对称指数。我们将AD-Ep组的结果与无癫痫的对照AD组（AD-NoEp）的结果进行了比较。
AD-Ep组包括8名个体，PET成像时的平均年龄为69.5±4.2岁。AD-NoEp组包括14名个体，PET成像时的平均年龄为71.7±9.8岁。在AD-Ep组中，我们发现tau蛋白沉积呈现高度不对称模式，致痫半球中的tau蛋白明显更多。致痫半球中的淀粉样蛋白沉积和皮质萎缩也更大，尽管与tau蛋白相比，不对称程度有所降低。与AD-NoEp组相比，AD-Ep组的tau蛋白不对称性明显更大，淀粉样蛋白和萎缩的不对称性有增加趋势。与AD-NoEp组相比，AD-Ep组双侧的淀粉样蛋白负荷也明显更大，致痫半球内的tau蛋白负荷有增加趋势。
我们的结果揭示了AD临床早期致痫灶与tau蛋白沉积、淀粉样蛋白沉积和神经退行性变之间的空间关联。在样本量较小的横断面研究的局限性内，这些发现有助于我们理解AD的临床病理异质性，证明了AD中局灶性癫痫与侧化病理学之间的关联。
