Cognitive and Biomarker Signatures of Late-Onset Temporal Lobe Epilepsy

Association Between Alzheimer Pathology, Sleep, and Cognition in Patients With Late-Onset Unexplained Epilepsy.

BACKGROUND AND OBJECTIVES Late-onset unexplained epilepsy (LOUE) has been linked to accelerated cognitive decline. However, the role of neurodegenerative proteins and whether they exert their effects through sleep-related mechanisms remain unexplored in this population. The goal of this study was to investigate the association of plasma p-tau217, a measure of Alzheimer disease (AD) pathology, with cognition in LOUE and its association with sleep. METHODS Participants with LOUE, with new-onset unprovoked seizures, age at onset 55 years or older, and absence of cortical lesions on MRI, were prospectively recruited. They underwent cognitive testing which included the extended Preclinical Alzheimer Cognitive Composite (PACC5). A 24-hour EEG was obtained, and sleep manually scored. Measures of sleep macroarchitecture and N2/N3 microarchitecture were extracted including slow oscillation (SO), fast spindle (FS), slow spindle (SS), and spindle-SO coupling measures. RESULTS Eighty-five participants enrolled (mean age 71.3 ± 7.1 years; 49% female). The average PACC5 Z score (±SD) was -0.63 ± 1.0. Higher plasma levels of log-transformed p-tau217 (per 1 unit increase) were associated with poorer cognition, PACC5 (β = -0.66; 95% CI -1.19 to -0.13; p = 0.0017), after adjusting for age, sex, and education. The severity of epilepsy modulated this relationship: individuals with both elevated p-tau217 and medication-refractory epilepsy exhibited worse cognitive performance (refractory epilepsy * p-tau217 interaction term β = -1.49; 95% CI -2.94 to -0.05; p = 0.04). Higher plasma p-tau217 levels were associated with reduced spindle-SO coupling. Mediation analysis indicated that approximately 24% of the association between p-tau217 and cognition was accounted for by spindle-SO coupling (95% CI 3%-85%, p = 0.032). DISCUSSION In individuals with LOUE, elevated plasma p-tau217 was associated with both cognitive impairment and disrupted sleep microarchitecture, with the most pronounced cognitive deficits observed in individuals with medication refractory epilepsy. These findings support the utility of plasma p-tau217 as a biomarker in this population and underscore the role of sleep processes in the relationship between neurodegenerative pathology and cognition in older adults with epilepsy.

Structural Brain Biomarkers for Identifying Progressive Amnestic Mild Cognitive Impairment

Objective. To identify the structural features of the brain in patients with amnestic mild cognitive impairment (aMCI) compared to healthy individuals, as well as to detect structural markers of progression to dementia in aMCI subgroups with different clinical outcomes. Materials and Methods. 41 patients with aMCI (mean age 71.5{+/-}9.5 years, 33 females) who underwent clinical assessment during 1 year follow-up, and 38 healthy controls (mean age 63.7{+/-}11.7 years, 28 females) were included. MRI scans were acquired, and the cortical thickness in both hemispheres, as well as the volumes of subcortical structures and hippocampal subfields, were analyzed. Results. Patients with aMCI as a whole, as well as aMCI subgroups with different clinical outcomes, showed significantly smaller bilateral hippocampal volumes and volumes of several hippocampal subfields than healthy controls. In addition, patients who were subsequently diagnosed with Alzheimer's disease dementia exhibited lower cortical gray matter thickness and smaller bilateral amygdala volumes than the healthy controls. Several subcortical structures and hippocampal subregions remained preserved in patients with aMCI, including those with unfavorable clinical outcomes. Conclusion. The study revealed structural brain abnormalities in aMCI, characterized by reduced hippocampal and hippocampal subfield volumes, as well as amygdala volume reduction, while other subcortical structures were relatively preserved. Furthermore, reduced cortical gray matter thickness may serve as a potential prognostic marker for conversion to dementia in patients with aMCI.

Instrumental, Neurophysiological, cognitive and Sleep InvestiGations into the High risk of neurodegeneraTion in Late Onset Epilepsy of Unknown aetiology: the INSIGHT-LOEU study.

This strategy could improve the early detection of cognitive decline, guide personalised management, and ultimately enhance quality of life, while contributing to the long-term sustainability of healthcare systems in an ageing population, focusing on LOEU as a model for dementia prevention.

EOAD-Signature Atrophy Predicts Dementia in Early-Onset MCI due to Alzheimer Disease

Background and Objectives Early-onset Alzheimer disease (EOAD) is associated with substantial variability in clinical progression, and reliable biomarkers to predict the transition from mild cognitive impairment (MCI) to dementia remain limited. Structural MRI measures have demonstrated prognostic value in late-onset Alzheimer disease, but their utility for predicting progression in EOAD is less well understood. The goal was to examine whether baseline cortical atrophy predicts progression to dementia in patients with MCI because of EOAD. Methods This study included a well-characterized cohort of patients with EOAD enrolled in the large multisite natural history Longitudinal Early-Onset Alzheimer's Disease Study. Participants underwent standardized clinical assessments and structural MRI at baseline. Participants were aged between 40 and 64 years with biomarker-supported sporadic EOAD at the MCI stage. Cortical atrophy was measured within the EOAD-signature, a set of predominantly parieto-temporal regions showing greater atrophy in EOAD than in controls. Clinical severity was measured with the global Clinical Dementia Rating. Cox proportional hazards models estimated the association between baseline EOAD-signature atrophy burden and the hazard of progression to dementia over time. We evaluated whether EOAD-signature atrophy improved prognostic performance beyond baseline clinical severity using likelihood ratio tests, Akaike Information Criterion (AIC), and Harrell concordance index. Results A total of 130 patients with MCI due to EOAD (mean age 59.6 ± 4.1 years; 49% female) and 97 cognitively normal controls (mean age 56.9 ± 6.0 years; 64% female) were included. Greater baseline atrophy within the EOAD-signature predicted faster progression to dementia (hazard ratio [HR] = 1.24 per 1-SD increase in atrophy; 95% CI 1.13–1.37; p < 0.002). Adding EOAD-signature atrophy burden to a model including baseline clinical severity significantly improved model fit (ΔAIC = −4.5; likelihood ratio test p = 0.011). Discussion Baseline cortical atrophy within the EOAD-signature predicts progression from MCI to dementia in EOAD and provides prognostic information beyond baseline clinical severity. These findings support the potential value of EOAD-signature atrophy as an MRI-based biomarker for individualized prognostication and clinical trial stratification.

HIPPOCAMPAL TAU-RELATED SIGNAL INDEXES HYPEREXCITABILITY AND NREM SLEEP–MEMORY DYSFUNCTION IN TEMPORAL LOBE EPILEPSY

Atypical Alzheimer disease: a multi-axis framework toward defining heterogeneity.