Authors :
Presenting Author: Astrid Devulder, – KU Leuven, University Hospitals Leuven
Tom Theys, MD, PhD – Research Group Experimental Neurosurgery and Neuroanatomy and Department of Neurosurgery – KU Leuven, University Hospitals Leuven; Greet Vanderlinden, PhD – Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology and Division of Nuclear Medicine – KU Leuven, University Hospitals Leuven; Koen Van Laere, MD, PhD – Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology and Division of Nuclear Medicine – KU Leuven, University Hospitals Leuven; Rik Vandenberghe, MD, PhD – Laboratory for Cognitive Neurology and Department of Neurology – KU Leuven, University Hospitals Leuven; François-Laurent De Winter, MD, PhD – Research Group Psychiatry, Department of Geriatric Psychiatry – KU Leuven, University Psychiatric Center (UPC) KU Leuven; Wim Van Paesschen, MD, PhD – Laboratory for Epilepsy Research and Department of Neurology – KU Leuven, University Hospitals Leuven
Rationale:
Misfolded hyperphosphorylated tau accumulates as neurofibrillary tangles in Alzheimer’s disease (AD) with a predilection for the mesial temporal structures in the early disease stage.
Previous in vitro and in vivo animal studies have revealed a role of neuronal hyperexcitability in the release and spread of tau in AD pathophysiology (Wu et al. 2016; Braak et al. 1995; Bejanin et al. 2017). Our aim was to record interictal epileptiform discharges (IEDs) and seizures using foramen ovale (FO) electrodes, and to assess the association between neuronal hyperexcitability and tau accumulation in the brain in patients with AD.
Methods:
We included four patients with mild cognitive impairment (MCI) and one patient with moderate AD, without a diagnosis of epilepsy. All participants underwent a previous 24 hours ambulatory scalp EEG, which showed rare IEDs in the four patients with MCI. The participant with moderate AD had a normal EEG, but a positive Reutens Questionnaire for clinical seizure diagnosis. All five participants were implanted with bilateral FO electrodes to obtain recordings from mesial temporal lobe structures. Scalp EEG according to the 10-20 system was simultaneously recorded for at least three consecutive days. All participants underwent a 30-minute
18F-MK-6240 PET/MRI with static acquisition 90 minutes post injection. Standardized uptake value ratio (SUVR) for the mesial temporal brain regions was calculated using inferior cerebellum as reference region to assess tau load distribution. Lateralization for tau load and IEDs was assessed by calculating an asymmetry index.
Results:
All five subjects had frequent and asymmetric IEDs on both FO electrodes.
≥ 95% of FO IEDs were not visible on scalp EEG. We recorded two hippocampal seizures in the patient with moderate AD, which were not visible on scalp EEG. While the total number of FO IEDs did not correlate with the total mesial temporal tau load for individual patients, we found in all subjects a congruence between the side of predominant mesial temporal 18F-MK-6240 binding SUVR and lateralization of mesial temporal IEDs. Conclusions:
We provide evidence that neuronal hyperexcitability in mesial temporal brain regions can be present early in the AD course. This epileptic activity was not detectable on scalp EEG, and corresponded with the lateralization of tau accumulation in mesial temporal brain regions. These findings have important implications in AD pathogenesis and the search for therapeutic targets.
Funding:
Bijzonder Onderzoeksfonds (BOF) KU Leuven [C24/18/097]