海馬硬化を伴う内側側頭葉てんかん

Epilepsy affects > 50 million people worldwide and is associated with a disproportionate burden of cognitive impairment. Emerging evidence suggests that neurodegenerative proteinopathies, particularly hyperphosphorylated tau (p-tau) and amyloid-β (Aβ), may contribute to cognitive dysfunction in people with epilepsy (PWE), even in the absence of dementia. However, the prevalence, distribution, and clinical significance of these proteins in epilepsy remain unclear. We conducted a systematic review of neuropathological studies examining neurodegenerative pathology in PWE without primary neurodegenerative disease. The review followed PRISMA guidelines and was registered with PROSPERO (CRD42024612990). A search of PubMed/MEDLINE, Ovid MEDLINE, Ovid Embase, and the Cochrane was performed from database inception to 7/8/2024. Eligible studies included human observational studies, case series, and post-mortem or surgical pathology assessing p-tau, amyloid, TDP-43, or related proteinopathies in PWE. Two reviewers independently screened studies, extracted data, and assessed risk of bias. Forty-two studies met the inclusion criteria. Most studies involved drug-resistant temporal lobe epilepsy (TLE) with hippocampal sclerosis. P-Tau was the most consistently reported finding, identified across multiple epilepsy types with a prevalence ranging from 3%-95%. Amyloid was detected less consistently but occurred in both temporal and extratemporal epilepsies. Several studies reported associations between p-tau burden and seizure frequency, epilepsy duration, and cognitive impairment, particularly in mesial TLE, although findings were heterogeneous. Neurodegenerative pathology, especially p-tau, is frequently observed in epilepsy and may represent a biological link between seizures, hyperexcitability, and cognition. These findings suggest that epilepsy may intersect with neurodegenerative mechanisms and underscore the need for studies integrating neuropathology, biomarkers, and cognitive outcomes.

Temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) poses significant challenges in therapeutic management. While studies have demonstrated seizure-induced alterations in peripheral immune molecules, the complement system, a central component of immune function, remains insufficiently characterized at single-cell resolution and spatial distribution in TLE-HS. This study aimed to comprehensively investigate the spatiotemporal dynamics of complement system components and their clinical implications in patients with TLE-HS. We first identified patterns of complement activity changes in epilepsy using bulk RNA sequencing. Then, we employed a TLE-HS mouse model for single-cell RNA sequencing and S1000 high-resolution spatial transcriptomics. We performed integrative bioinformatic analyses on single-cell data to quantify complement-system activity and define microglial heterogeneity, leading to the identification of complement-associated microglial subpopulations. Spatial transcriptomic data then validated the anatomical localization of these identified subpopulations. Finally, we developed and evaluated two machine-learning models based on complement-related gene signatures. Complement activity was elevated in epilepsy. The levels were higher in hippocampal sclerosis (HS) tissue than in normal hippocampus. They were also increased in mesial temporal lobe epilepsy with hippocampal sclerosis compared with mesial temporal lobe epilepsy without hippocampal sclerosis, and in patients with high seizure frequency (HSF) compared with those with low seizure frequency (LSF). Complement-related signatures were further associated with antiseizure medication response. Candidate biomarkers including IRF2, GNB2, EHD1, CTSB, and CFH were identified using statistical modeling and machine learning. Among multiple classifiers, the support vector machine model showed the best predictive performance, and SHAP analyses indicated distinct contribution directions for these candidate genes. In the kainic acid (KA) mouse model, single-cell analyses showed that complement activity was upregulated across cell types in HS. Microglia exhibited the highest complement activity. Re-clustering and trajectory inference defined HS-associated microglial subpopulations that were enriched in terminal differentiation states. hdWGCNA together with differential expression highlighted Ctsb, C1qa, and Fcer1g as core complement-linked genes. Using Ctsb-defined microglial states, eight diagnostic biomarkers were selected, and a multi-layer perceptron model achieved superior classification accuracy in epilepsy diagnosis. Finally, cell-cell communication and spatial transcriptomics consistently implicated an Spp1-related signaling axis associated with Ctsbhigh microglia in hippocampal sclerosis regions. The resulting diagnostic and response-prediction models were deployed as exploratory web-based research tools pending independent validation. Our study systematically characterized the complement system in TLE-HS by integrating multi-level omics data, including bulk RNA sequencing, single-cell sequencing, and spatial transcriptomics. We revealed the potential value of complement system gene signatures in clinical diagnosis and personalized treatment of epilepsy.

Mesial temporal lobe epilepsy (mTLE) is a subtype of focal epilepsy in which approximately one-third of patients develop pharmaco-resistance, likely driven by multiple mechanisms including structural changes and dysregulated non-coding RNAs (ncRNAs). However, our understanding of the contribution of ncRNAs to mTLE pathogenesis remains incomplete, and many classes remain uncharacterized. Notably, transfer RNAs (tRNAs) and their stress-induced fragments are emerging as important regulators of gene expression and candidate fluid-based biomarkers. However, their tissue-level expression and role in disease pathogenesis remain poorly understood. Therefore, in this study we performed profiling of tRNA and tRNA-derived fragments (tRFs), in human hippocampal and cortical samples from hippocampal sclerosis mTLE (mTLE-HS) and non-hippocampal sclerosis mTLE (mTLE non-HS) patients and postmortem controls by total RNA sequencing (RNA-seq) and small non-coding RNA sequencing (sncRNA-seq). Our data reveal widespread changes in the neural expression of pre-tRNA, tRNA and tRF expression in human mTLE brain tissue. One of the most prominent changes observed was a downregulation of 5' fragments derived from tRNA-His-GTG. Knockdown of this tRNA and its 5' fragments combined with total RNA-seq in neuronal cells identified 5'tRNA-His-GTG fragments as strong regulators of gene expression, including of epilepsy-associated genes. For example, Cannabinoid Receptor 1 (CNR1) was identified as a possible downstream target of 5'tRF-His-GTG. To investigate the contribution of 5'tRF-His-GTG to TLE pathogenesis and seizure activity, the increased expression of this tRF that was observed at 24 h after status epilepticus (SE) in mice was targeted using inhibitors. This induced increased seizures and altered network activity, with reduced theta and alpha power bands, and enhanced glial fibrillary acidic protein (GFAP) expression. Together, our study confirms and extends previous findings by identifying widespread changes in human brain tRF expression in mTLE and demonstrates for the first time that tRF manipulation affects seizure activity and mTLE pathology.

BACKGROUND: Balancing seizure outcomes and cognitive deficits is always a challenge in both mesial and neocortical temporal lobe epilepsy cohorts. The present study evaluated the long-term seizure outcomes and perceived quality of life (QOL) in both of these groups, along with factors predictive of these outcomes. METHODS: A retrospective analysis of patients undergoing temporal lobe epilepsy (TLE) surgery from 2015 to 2023, with at least 1 year of follow-up (N = 175), is presented. Patients were grouped as MTLE (mesial temporal sclerosis only) and NTLE (neocortical) based on neuroimaging. Surgical approaches included standard anterior temporal lobectomy with amygdalohippocampectomy (ATL + AH) and hippocampal-sparing resections. Seizure outcomes were classified using Engel's scale; QOL was assessed telephonically using a questionnaire adopted from QOLIE-10-P. Predictors for seizure freedom and perceived QOL outcomes were studied in both groups. RESULTS: At a mean follow-up of 55 months, 83.5% of patients achieved seizure freedom, MTLE (85%), and NTLE (81%) patients. Of the entire TLE cohort, 38% were free from drugs at the last follow-up. In MTLE, the presence of red flags significantly lowers the chances of complete seizure freedom (59% vs. 93%.) (OR 0.11, 95% CI 0.03-0.37; p < 0.001). Preserving the hippocampus in NTLE is associated with a lower the seizure freedom rate (68% vs. 86%) (OR 0.34, 95% CI 0.10-1.08). In NTLE, the odds of perceived memory decline were marginally higher in the standard ATL + AH group (OR 1.48, 95% CI 0.37-5.87) compared to hippocampus-preserving resection (p = 0.7). Approx. 75% patients reported improvement in all QOL parameters in the entire TLE cohort. No mortality or permanent neurological deficits recorded. CONCLUSIONS: TLE surgery provides robust seizure control and significant perceived QOL improvements for most patients in the long term. Hippocampal sparing surgery in NTLE did not seem to affect perceived memory difficulties but was more likely to be associated with suboptimal seizure outcomes.

BACKGROUND: Epileptogenesis transforms a healthy brain into an epileptic network, yet the temporal and cell-type-specific molecular events driving this transition remain poorly defined. Neuron-glia interactions are essential in this process, but no study has systematically charted their transcriptional dynamics from the acute insult to chronic epilepsy. METHODS: Using the intracortical kainic acid mouse model that recapitulates key hallmarks of mesial temporal lobe epilepsy with hippocampal sclerosis in humans, we performed Fluorescent Activated Nuclear Sorting of NeuN+ (neuronal) and NeuN⁻ (glia) nuclei followed by RNA sequencing at 1 h, 24 h, and 3 months after status epilepticus. Differential expression and integrative GO/KEGG analyses resolved stage-specific molecular programs across cell types. RESULTS: The majority of genes differentially expressed in neurons and glia were exclusive to the respective time point investigated. We also identify a sequential reorganization of cellular gene expression changes during epileptogenesis. The acute phase is dominated by a shared stress response and DNA-repair programs in both neurons and glia. At 24 h, glia undergoes a marked transcriptional pivot involving necroptosis-associated, TNFR1/IFN-linked, and COX-2/chemokine pathways, while neurons display immune- and plasticity-related signatures. By 3 months, transcriptional activity is largely confined to glia and enriched for inflammatory, angiogenic, and gliogenic processes, consistent with long-term neurovascular remodeling. Only a few transcripts, including Parp3 (neurons) and Tlr1 (glia), are dysregulated across all stages. CONCLUSION: These findings reveal an orderly transition from an acute protective-leaning program to a early latent glial inflammatory/regulated-death state, culminating in chronic gliopathy. Our work provides, to our knowledge, the first cell-type-resolved temporal atlas of epileptogenesis and identifies the early latent phase as a mechanistically tractable window for antiepileptogenic intervention.