Association of Seizure Foci and Location of Tau and Amyloid Deposition and Brain Atrophy in Patients With Alzheimer Disease and Seizures

Abstract

Background and objectives: 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.

Methods: 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).

Results: 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.

Discussion: 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.

Figure 1. Representative Tau and Amyloid PET Images for AD-Ep Group

(A) Representative tau PET images. Axial slices are shown for each participant (Pt), arranged from inferior (left) to superior (right). Images are oriented such that the epileptogenic hemisphere for each participant is shown on the left. (L) and (R) indicate the epileptogenic hemisphere (left or right, respectively) for each participant. Participant 1 was imaged using ¹⁸F-flortaucipir while participants 2–8 were imaged using ¹⁸F-MK-6240. (B) Representative amyloid PET images. Image orientation is the same as for (A), and all participants were imaged using ¹¹C-PIB. White arrows highlight subtler regions of increased tau or amyloid deposition in the epileptogenic hemisphere while yellow arrows highlight increased amyloid in the contralateral hemisphere in some participants.

Figure 2. Asymmetry Indices for Tau, Amyloid, and Cortical Atrophy in the AD-Ep Group

AIs were calculated with respect to the epileptogenic/nonepileptogenic hemisphere across 6 large brain regions, for (A) tau deposition, (B) amyloid deposition, and (C) cortical atrophy. A positive AI indicates greater tau deposition, amyloid deposition, or cortical atrophy in the epileptogenic hemisphere whereas a negative AI indicates greater tau deposition, amyloid deposition, or cortical atrophy in the nonepileptogenic hemisphere. Box-and-whisker plots for the AD-Ep population are shown, and individual AD-Ep participants are plotted as colored markers, based on whether their seizures arose from the left (blue) or right (red) hemisphere. AIs for tau and amyloid were calculated using partial volume–corrected SUVR and DVR values, respectively. Numbers above each ROI represent the number of participants in whom AIs could be calculated for that ROI (i.e., participants with above-threshold SUVR or DVR levels). Asterisks denote ROIs in which the AI was significantly different from 0 (FDR-corrected p value < 0.025), whereas asterisks in parentheses indicate trends toward significance. Note in part (A), on the occipital plot, participant 5 is plotted on the x-axis (blue filled circle at tau AI = −40), although this participant had a much larger magnitude of AI (> −100) that otherwise would not be seen due to the scaling of the plot (but can be seen in Figure 3A). AI = asymmetry index; DVR = distribution volume ratio; SUVR = standardized uptake value ratio.

Figure 3. Comparison of Tau Asymmetry, Amyloid Asymmetry, and Atrophy Asymmetry Between AD-Ep and AD-NoEp Groups

AIs were calculated with respect to the left hemisphere across 6 large brain regions, for (A) tau deposition, (B) amyloid deposition, and (C) cortical atrophy. A positive AI indicates greater tau deposition, amyloid deposition, or cortical atrophy in the left hemisphere while a negative AI indicates greater tau deposition, amyloid deposition, or cortical atrophy in the right hemisphere. Box-and-whisker plots are shown for the AD-NoEp group, with values for each AD-NoEp participant plotted as open black circles. AD-Ep participants are plotted using colored markers, based on whether their seizures arose from the left (blue) or right (red) hemisphere. AIs for tau and amyloid were calculated using partial volume–corrected SUVR and DVR values, respectively. AD-Ep participant 1 was excluded from the tau analysis because their tau PET imaging was performed using FTP, rather than with MK-6240. Blue asterisks denote ROIs in which the AI for AD-Ep participants with left-sided seizures was significantly greater than for AD-NoEp (FDR-corrected p value < 0.025), whereas blue asterisks in parentheses indicate trends toward significance. AI = asymmetry index; DVR = distribution volume ratio; SUVR = standardized uptake value ratio.

Figure 4. Comparison of Tau Burden, Amyloid Burden, and Cortical Thickness Between AD-Ep and AD-NoEp Groups

(A) Tau burden. MK-6240 SUVRs (PVC) were averaged across 6 large brain regions in the left hemisphere (left) and right hemisphere (right). The AD-NoEp distribution is shown as a box-and-whisker plot, with values for AD-NoEp participants plotted as open black circles. Values for AD-Ep participants are plotted using colored markers, based on whether their seizures arose from the left (blue) or right (red) hemisphere. Participant 1 was excluded from the tau analysis because their tau PET imaging was performed using FTP, rather than with MK-6240. (B) Amyloid burden. Format is similar to (A) but uses PIB DVRs (PVC). (C) Cortical thickness. Format is similar to (A). Blue asterisks represent statistically significant differences between AD-Ep participants with left-sided epilepsy and the AD-NoEp group (FDR-corrected p value < 0.025). Blue asterisks in parentheses represent trending differences between these groups. DVR = distribution volume ratio; PIB = Pittsburgh Compound B; PVC = partial volume correction; SUVR = standardized uptake value ratio.