Annals of Neurology最新文献

Objective: The pharmacological treatment of temporal lobe epilepsy (TLE), a disorder characterized by recurrent seizures and cognitive dysfunction, is limited to symptomatic control. Identifying novel targets to modify disease progression is of great clinical and translational interest. Cellular senescence has been recently implicated in the development and progression of other neurodegenerative diseases, but its role in TLE is unstudied.

Methods: We first investigated cellular senescence markers in resected hippocampi from patients with medically intractable TLE through multiplexed immunofluorescence. We next used a mouse model of TLE (pilocarpine induced status epilepticus [SE]) for a combination of immunohistochemistry, behavioral testing, and electroencephalogram (EEG) monitoring. We implemented 2 strategies for removal of senescent cells (SCs), a genetic mouse model allowing for targeted senolysis, and a pharmacological approach using dasatinib and quercetin.

Results: We found a 5-fold elevation of senescent glia in human TLE cases as compared with controls. In mice, we found increases in senescence markers at both the transcript and protein level and predominantly expressed in microglia, which developed within 2 weeks following SE. Senolytic treatment produced a 50% reduction in SCs, rescued long-term potentiation deficits, normalized spatial memory impairments, reduced seizures, and protected a third of animals from epilepsy.

Interpretation: Our data demonstrate that SCs accumulate in both human TLE and in a mouse model of TLE and suggest that clearing SCs may be a viable strategy to reduce seizures and associated cognitive comorbidities. ANN NEUROL 2025.

Objective: The objective of this study was to characterize the phenotypic spectrum of the rare sporadic Creutzfeldt-Jakob disease cortical subtype (sCJDMM/MV2C) in a large multicentric autopsy cohort.

Methods: We evaluated clinical histories, biofluid markers, brain diffusion-weighted (DW)-magnetic resonance imaging (MRI), and electroencephalogram (EEG) findings in 56 patients. The histomolecular assessment included misfolded prion protein (PrP) typing by immunoblotting, histopathology, and PrP immunohistochemistry in several brain areas.

Results: Misfolded PrP typing showed a dominant 19 kDa unglycosylated PrP fragment (type 2) in all brains, focally associated with a 21 kDa (type 1) fragment in 53% of participants (MM/MV2C + 1). Immunohistochemistry revealed coarse/perivacuolar PrP deposits in the neocortices and a patchy/coarse pattern in the cerebellar molecular layer. The mean disease duration was 16.0 months. At onset and early stages, most patients manifested only progressive cognitive decline, consistent with the predominant distribution and relative severity of spongiform change in the cerebral cortex. Brain DW-MRI showed cortical hyperintensities in 94% of cases. Cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) assay was positive in 70% of cases. Compared with pure MM/MV2C, the mixed MM/MV2C + 1 phenotype showed a shorter disease duration (14 vs 19 months), and a higher frequency of striatal DW-MRI hyperintensity (56% vs 19%), EEG periodic sharp-waves complexes (41% vs 6%), and CSF RT-QuIC positivity (86% vs 53%).

Interpretation: The clinicopathologic phenotype of sCJDMM/MV2C diverges from that of typical sCJDMM/MV1. Moreover, the histomolecular heterogeneity within MM/MV2C influences clinical features and results of diagnostic investigations, challenging its identification in vivo. Nonetheless, results suggest that DW-MRI and CSF RT-QuIC allow an accurate clinical diagnosis of Creutzfeldt-Jakob disease in most patients. ANN NEUROL 2025.