Abstracts

Rationale: Evidence from animal and human studies has demonstrated that neuronal hyperexcitability is an important feature in the pathophysiology of Alzheimer's disease (AD). Subclinical epileptiform activity has emerged as a scalp EEG biomarker of neuronal hyperexcitability in early stages of AD. Whether epileptiform abnormalities are common in early stages of sporadic AD, and how these electrical abnormalities relate to clinical seizures in this population remains unclear.  Methods: We performed 24-hour ambulatory scalp EEGs on 36 cognitively normal healthy controls (HC), 31 early stage AD with no history of epilepsy (AD-NoEp), and 10 early stage AD with late-onset epilepsy related to AD (AD-Ep).  Participants were between 50-90 years old (median 73) and were recruited from the Massachusetts Alzheimer’s Disease Research Center and memory disorders/epilepsy clinics at our institutions.  Electrodes were placed according to the international 10-20 system with T1/T2 anterior temporal electrodes. Two epileptologists, blinded to diagnosis, visually reviewed all EEGs and annotated all potential epileptiform abnormalities. A panel of 10 epileptologists, also blinded to diagnosis, was then surveyed to generate a consensus interpretation of epileptiform abnormalities in each EEG. Results: Based on consensus interpretation, epileptiform abnormalities were common in AD, occurring in 50% of AD-Ep and 26% of AD-NoEp groups, compared to only 8% of HC. Location of epileptiform abnormalities was left temporal in HC; left temporal and bi-frontal in AD-NoEp, and bi-temporal in AD-Ep. Clinical seizures in AD-Ep were associated with epileptiform discharges with specific features, including more frequent occurrence, robust morphology, occurrence during wakefulness, and right temporal location. In AD-Ep participants with epileptiform discharges, the severity of seizure semiology scaled with the frequency of epileptiform discharges, with the lowest rates of epileptiform discharges associated with focal aware seizures, and the highest rates associated with generalized convulsions. We also examined scalp EEG biomarkers of mesial temporal lobe hyperexcitability in AD. Temporal intermittent rhythmic delta activity (TIRDA) was common and lateralized to the same side as epileptiform discharges. Moreover, frequent unilateral small sharp spikes (SSS), when present, shared the same lateralization as epileptiform discharges and seizures, and thus likely represent an epileptiform variant in AD.  Conclusions: Our results point to an electroclinical spectrum of hyperexcitability in AD, ranging from EEG biomarkers of mTL hyperexcitability to subclinical epileptiform discharges to clinical seizures. The frequency, morphology, and spatiotemporal characteristics of epileptiform discharges are closely related to the clinical expression of seizures in AD. Moreover, the specific localization of epileptiform abnormalities suggests that hyperexcitable brain substrate in AD may be linked to disease pathology. Funding: ADL was funded by NIH NINDS K23 NS101037 and R25 NS065743, and the American Academy of Neurology Institute. RAS was funded by the AJ Trustey Epilepsy Research Endowed Fund. JJ was funded by a grant from SAGE Therapeutics. MBW was funded by NIH NINDS 1K23NS090900, 1R01NS102190, 1R01NS102574, and 1R01NS107291. SSC was funded by NIH NINDS R01 NS062092 and K24 NS088568.