Plasma P-Tau217 Linked to Cognitive Decline and Sleep Disruption in Late-Onset Unexplained Epilepsy

Rani Sarkis, MD, MSC

(Credit: Brigham and Women’s Hospital)

A new study recently presented at the 2024 American Epilepsy Society Annual Meeting, held December 6-10, in Los Angeles, showed that plasma ptau217 negatively correlated with measures of verbal memory and sleep microarchitecture but not hippocampal volume in patients with late-onset unexplained epilepsy (LOUE). These results suggest the utility of plasma ptau217 as a biomarker in this patient population, and highlighted the close link between neurodegenerative proteins, sleep integrity, and cognition in older patients with epilepsy.¹

Among 63 participants (mean age, 70.4 ± 7.0 years; women, 51%), the average Preclinical Alzheimer Cognitive Composite (PACC Z) score was -0.48 ± 0.92, and delayed verbal recall Z score was -0.73 ± 1.22. Results revealed that plasma p-tau217 negatively correlated with delayed verbal recall (β = -0.09; P = .0073) and demonstrated a trend for negative association with the PACC (β = -0.05; P = .06) when investigators controlled for age, sex, and years of education.

“Plasma biomarkers are soon going to be available for clinical use, and their relevance in aging research is becoming more established. It was nice to see that they also correlate with cognitive performance in individuals with late onset unexplained epilepsy, and that a possible biological explanation for this association is that they are affecting sleep architecture,” lead author Rani Sarkis, MD, MSC, neurologist and director of neurophysiology education for neurology residents at Brigham and Women’s Hospital, told NeurologyLive^®.

In this study, investigators prospectively recruited participants from Brigham and Women’s Hospital and affiliated hospitals who had new-onset seizures in 5 years, were aged at least 55 years, had an absence of cortical lesions on MRI and provoking factors. Participants underwent a neuropsychological battery which included the PACC-5, authors noted that the Z scores were generated from a control population from the Harvard Aging Brain Study with a similar age range. Additionally, researchers extracted a delayed verbal recall Z score by combining the 2 memory tests from the PACC.

READ MORE: Interim Analysis Highlights Long-Term Safety of Azetukalner for Focal Epilepsy

All told, a 24-hour electroencephalogram was obtained in 1 year of cognitive assessment from the participants. Investigators had sleep manually scored, and then had sleep spindle features extracted using Luna software at the F3 and C3 electrodes. Authors noted that measures of interest for the 11 and 15 Hz frequencies included slow oscillation (SO) coupled spindle density (per minute), magnitude of spindle-SO coupling, and number of spindles overlapping a SO. Moreover, researchers obtained a volumetric MRI in 1 year of testing and processed to extract hippocampal volume using Freesurfer software. Notably, investigators drew plasma p-tau217 on the day of cognitive testing.

Additional findings showed that plasma p-tau217 negatively correlated with measures of 11Hz spindle-SO coupling at F3, and measures of 11Hz and 15Hz spindle-SO coupling at C3 when researchers controlled for age and sex. Furthermore, the results did not show an association between p-tau217 levels and hippocampal volume (β = -0.000001; P = .63). “We are showing that this biomarker is useful in this patient population, and we hope these findings can be replicated in other cohorts. At some point this might be a test that can be ordered in clinic if someone fails a cognitive screen, and this will guide future testing and possibly treatment options,” Sarkis said.

“We will be exploring the relationship between this biomarker and brain volume, and whether this predicts cognitive decline as we are following this cohort for 3 years,” Sarkis noted. “Ultimately, if someone has an unexplained seizure, what are some newer tests we should be thinking about when they first get evaluated in clinic which can help us understand why they had the seizure, and what their prognosis is going to be. I think plasma ptau217 is going to be one of those tests.”

Previous research has demonstrated an association with accelerated cognitive decline and an increased risk of developing dementia in LOUE.² Plasma p-tau217, a novel biomarker, has been shown to correlate with tau pathology and amyloid positron emission tomography findings in Alzheimer disease and to exhibit elevated levels in patients with worsening cognitive function. This suggests its potential utility as a screening tool in epilepsy clinics.³ Furthermore, evidence indicated that sleep microarchitecture is closely linked to cognitive status in older adults.⁴ Disruptions in sleep microarchitecture may represent a mechanism through which neurodegenerative proteins, such as p-tau217, influence cognitive decline.

Click here for more AES 2024 coverage.

REFERENCES
1. Sarkis R, Liu L, Orozco J, et al. Higher Plasma p-tau217 Correlates with Worse Cognition and Sleep Microarchitecture Integrity in Late Onset Unexplained Epilepsy. Presented at: AES 2024; December 6-10; Los Angeles, CA.
2. Tsai ZR, Zhang HW, Tseng CH, et al. Late-onset epilepsy and subsequent increased risk of dementia. Aging (Albany NY). 2021;13(3):3573-3587. doi:10.18632/aging.202299
3. Aguillon D, Langella S, Chen Y, et al. Plasma p-tau217 predicts in vivo brain pathology and cognition in autosomal dominant Alzheimer's disease. Alzheimers Dement. 2023;19(6):2585-2594. doi:10.1002/alz.12906
4. Parker JL, Appleton SL, Melaku YA, et al. The association between sleep microarchitecture and cognitive function in middle-aged and older men: a community-based cohort study. J Clin Sleep Med. 2022;18(6):1593-1608. doi:10.5664/jcsm.9934