Authors :
Presenting Author: Yue-Loong Hsin, MD – Chung Shan Medical University Hospital
Pen-Fu Kao, MD, PhD – Nuclear Medicine – Chung Shan Medical University Hospital; Min-Fei Chuang, MD – Neurology – Chung Shan Medical University Hospital; Wentai Liu, PhD – Bioengineering – University of California, Los Angeles
Rationale: Late-onset epilepsy (LOE) has diverse causes, including Alzheimer's disease (AD). Epilepsy may appear at various AD stages and precede dementia onset. Early-onset epilepsy (EOE) and LOE in middle-aged/older individuals relate to aging-related concerns, including heightened AD risk. Amyloid-beta (Aβ) peptide, a defined pathology of AD, has been shown to play a role in epileptogenesis. This study aims to provide an integrated perspective by prospectively investigating the relationship between various clinical variables and cerebral Aβ accumulation in a cohort of middle-aged and older individuals with epilepsy.
Methods: Patients aged over 45 with uncomplicated epilepsy were enrolled, adhering to the criteria for non-lesional MRI results. Aβ deposition was assessed using [18F]florbetaben (FBB) PET and CT scans. The FBB standard uptake value ratio (SUVR) in specific brain regions was quantified and converted to composite SUVR and Centiloid (CL) using established methods. Cognitive decline was monitored using the mini-mental state examination (MMSE). Some participants underwent APOE genotyping via whole-exon sequencing, excluding common mutations associated with dementia and epilepsy.
Results: We studied 46 patients (mean age: 64.3 ± 9.8 SD), with 25 having onset age above 40 years, followed for 37.1 months post-amyloid PET. Eighteen were drug-resistant (needing > two antiseizure meds); four initially had AD, five developed dementia. Age correlated positively with CL (p < 0.01). Onset age (6 to 82 years) and CL highly correlated (p < 0.01), while disease duration (1 to 60 years) negatively correlated with CL (p < 0.05). CL scales inversely related to initial MMSE and MMSE change (p < 0.01). ROC found predictive CL threshold of 1.8 for cognitive decline (≥ 3 MMSE decrease). ROC curves highlighted strong predictive regions: the prefrontal cortex, anterior cingulate gyrus, and post-cingulate precuneus (AUC > 0.85) (Figure 1). Focusing on LOE (onset > 40) without cognitive decline, logistic regression found higher SUVR values in bilateral mesial/lateral temporal and right prefrontal regions. An 81-year-old patient's PET showed high Aβ in regions corresponding to EEG epileptic discharges (Figure 2A), yet no cognitive decline. Figures 2B and 2C show similar-aged patients; one with later epilepsy onset and Aβ deposition had faster cognitive decline. Genotyping revealed 20.6% carried at least one -ε4 allele, with no significant seizure control difference. Amyloid burden (CL values) didn't significantly associate with drug resistance.
Conclusions: Our study explored the intricate interplay of clinical variables, treatment outcomes, and Aβ accumulation in middle-aged and older epilepsy patients. We especially unveiled distinct Aβ distribution patterns closely linked to AD progression. Patients with atypical Aβ patterns retained stable cognitive function. Aβ factors did not directly contribute to epilepsy treatment resistance. We propose classifying LOE into Aβ-related and non-Aβ-related categories, introducing the concept of "Beta-amyloid driven epilepsy."
Funding: Funded by Taiwan's Ministry of Education's Higher Education Sprout Project via the Center for Neuromodulation Medical Electronics Systems.