OBJECTIVE:New onset refractory status epilepticus (NORSE) is a rare, severe presentation of refractory status epilepticus (RSE), with approximately half of cases cryptogenic NORSE (c-NORSE). We compared electroencephalographic (EEG) findings alongside clinical features between NORSE and RSE not meeting NORSE criteria to better understand outcomes and prognostication. METHODS:This retrospective cohort study analyzed 81 RSE patients admitted to the intensive therapy unit (ITU) at the National Hospital for Neurology and Neurosurgery and University College London Hospital (2007-2023). Patients were categorized as RSE not meeting NORSE criteria (n = 52) or NORSE (n = 29). EEG features, treatment, and outcomes (ITU stay, mortality, cognitive outcome, and antiseizure medication [ASM] use), were evaluated. RESULTS:Of 29 NORSE patients (15 c-NORSE, 51.7%; 14 etiology-identified NORSE, 48.3%), autoimmune (20.7%) and infectious (17.2%) etiologies were most prevalent. Six-month mortality was higher in c-NORSE than etiology-identified NORSE (20.0% vs. 7.1%), but similar between NORSE and RSE not meeting NORSE criteria (13.8% vs. 21.1%). EEG analysis revealed longer seizure duration (mean = 243.38 vs. 51.67 s, p < .001), a tendency to higher seizure frequency (.013 vs. .009 seizures/min, p = .076), and increased presence of generalized periodic epileptiform discharges and stimulus-induced rhythmic, periodic, or ictal discharges in NORSE than RSE not meeting NORSE criteria. Across all patients, higher initial seizure burden correlated with longer ITU admissions and worse outcomes. Compared with RSE not meeting NORSE criteria, NORSE patients had longer ITU stays (median = 51 vs. 11 days, p < .001), more ASMs (mean = 3.91 vs. 2.00, p = .031), greater sedative use (mean = 2.17 vs. 1.00, p < .001), and more frequent cognitive impairment at discharge (88.9% vs. 62.2%, p = .037). SIGNIFICANCE:NORSE, particularly c-NORSE, tends to follow a more severe course than RSE not meeting NORSE criteria, with more severe background EEG features including the initial EEG, greater seizure burden, longer ITU stays, and increased incidence of cognitive impairment at discharge. Six-month mortality was similar, implying additional contributing factors to mortality.
Neural regeneration therapies aim to treat neurodegeneration by promoting the proliferation and maturation of exogenous or endogenous neural progenitor cells (NPCs). However, their efficacy has been limited. Deep brain stimulation (DBS) via implanted electrodes has been shown to promote neurogenesis in vitro and in vivo. Still, its invasiveness precludes deployment in research and widespread clinical use. Temporal interference (TI) has emerged as a strategy for non-invasive, high-precision DBS using multiple kHz-range electric fields to target the deep brain. Here, we validate the potential of TI stimulation for neural regeneration augmentation in the central nervous system (CNS). First, we showed that TI stimulation modulated at the theta-band frequency enhances the maturation of embryonic neural progenitor cells in vitro. We then demonstrate that theta-band TI stimulation targeting the hippocampus enhances endogenous hippocampal neurogenesis in an in vivo mouse model of Alzheimer's disease-like amyloidosis. By uncovering frequency-specific control of stem cell fate, we propose a clinically relevant regeneration strategy that avoids pharmacological or genetic manipulation. Our results enable focal, non-invasive augmentation of deep-brain neural regeneration via electrical stimulation.
Abstract Background Gait impairment is a hallmark symptom of Parkinson’s Disease (PD). Traditional clinical assessments cannot capture real-world motor fluctuations, as they are sparsely performed. We validated the use of nearables, passive sensing technologies, including Kinect RGB-D cameras and ultra-wideband (UWB) radar, for continuous, objective assessment of gait fluctuations in PD within a home-like setting. Methods Fifteen PD patients with mild symptoms and fourteen age- and sex-matched healthy controls (HC) performed 4-metre walking tasks in a living lab facility. Patients repeated the task during “ON” and “OFF” states of their daily medication cycle. Gait features, including stride length, stride time, and gait speed, were extracted from Kinect, radar, and a ground-truth smart floor. Data were analysed to assess inter-sensor agreements and group-level differences. Results Stride time demonstrated the highest agreement between devices ( r = 0.903), while stride length was weaker ( r = 0.779). Nevertheless, stride length from both Kinect and radar distinguished PD OFF from HC (camera q = 0.020; radar q = 0.005), and radar additionally differentiated ON from OFF ( q = 0.020). Neither device differentiated PD ON from HC, indicating medication reduced observable gait differences. Conclusions Although some spatial metrics show device discrepancies, both systems demonstrate sensitivity to gait patterns and medication-dependent changes, supporting their use for longitudinal, real-world monitoring of motor symptoms.
Plasma phosphorylated-tau217 (pTau217) is a blood-based biomarker of Alzheimer's Disease (AD) pathology. Cognitive resilience describes the presence of neurodegenerative pathology and preserved cognition. Cognitive resistance describes avoidance of neurodegeneration. This post hoc analysis of the Post-Operative Delirium Belfast (PODB) cohort aimed to define cognitive resilience using plasma pTau217 and Mini Mental State Examination (MMSE) measures. PODB was an observational cohort study, investigating people aged 65 and over, without a diagnosis of dementia, undergoing elective hip and knee replacement between 2012-2014 with subsequent long-term follow-up. In this analysis, pre-operative plasma pTau217 was used as a marker of neuropathology. A cutoff of 0.42 pg/mL was used (Ashton NJ et al. 2024). Pre-operative and 8-year follow-up MMSE scores were used as a marker of cognition. A score of ≥24 was considered preserved. Definitions used were: Cognitive resilience = pTau217 ≥0.42 pg/mL plus MMSE ≥24. Cognitive resistance = pTau217 <0.42pg/mL plus MMSE ≥24. Affected = pTau217 ≥0.42 pg/mL plus MMSE <24. Those with normal markers plus poor cognition were defined as pTau217 <0.42pg/mL plus MMSE <24. These four groups were identified at baseline and follow-up, respectively. In this analysis, 231 participants were included at baseline, 104 at follow-up. Of the n = 231 participants included at baseline, n = 147/231 (64%) were cognitively resilient, n = 65/231 (28%) resistant, n = 17/231 (7%) affected, and n = 2/231 (<1%) had normal markers and MMSE <24. Of the n = 104 participants with follow-up information included in this analysis, n = 61/104 (59%) were cognitively resilient, n = 33/104 (32%) were resistant, n = 8/104 (8%) affected, and n = 2/104 (<1%) had normal markers and MMSE <24. Cognitively resilient participants at baseline were younger ( p = 0.011) and tended to be female ( p = 0.977) compared to affected participants. At follow-up, those who were cognitively resilient tended to be younger ( p = 0.196) and female ( p = 0.212) compared to affected participants (Table 1). Of those cognitively resilient at follow up, n = 59/61 (97%) of these participants were also cognitively resilient at baseline. Using pTAu217, at the cut-off quoted, we found a high incidence of cognitive resilience in an older elective surgical cohort.
The pathological cascade of Alzheimer's disease (AD) begins decades before clinical symptoms, yet modelling this slow and progressive process in experimental systems has remained challenging. Current models largely depend on Tau mutations associated with primary Tauopathies and fail to reproduce AD-relevant neurofibrillary tangle formation, even when human Tau isoforms and amyloid pathology are combined. Here, we xenotransplanted human neurons into Rag2 −/− and Rag2 −/− App NL−G−F mice and exposed them to AD-derived Tau seeds via parenchymal brain injections, providing both the pathological nucleation event and the amyloid-rich environment needed to compress decades of human disease into the lifespan of a mouse. Whilst AD-Tau seeding alone was sufficient to induce Tau misfolding in human neurons, amyloid exposure markedly accelerated Tau aggregation, driving neurofibrillary tangle formation and elevated insoluble pTau181 and pTau231 in aged xenografts. This effect was abolished in human Tau-knockout neurons, although LAMP1 positive neuritic dystrophy persisted. Late-stage Tau pathology was absent in non-grafted App NL−G−F mice, indicating a unique human neuronal susceptibility to Tau aggregation. Together, these findings demonstrate that the human neuronal environment is a critical determinant of neurofibrillary tangle formation, and that amyloid causally accelerates this process, thereby establishing the Tau seeded xenograft model as a platform to dissect the interaction between amyloid and Tau in a human-relevant system.
