In 1969, the International League Against Merlis, Dr. D. David Daly of Dallas, Dr. Epilepsy published a scheme for classifica- Dieter Janz of Berlin, Dr. J. Kiftin Penry of tion of epileptic seizures. Professor H. Bethesda, Dr. Carlo Alberto Tassinari of Gastaut, then Secretary-General of ILAE Marseille. In addition, Dr. Rudolph Dreyer and a member of the Commission on Clas- of Bethel. Dr. Antonio V. Escueta of Los sification, related the history of the work Angeles, Dr. K. F. Masuhr of Berlin, Dr. which represents a milestone in efforts at Richard H. Mattson of New Haven, Dr. classifying epileptic seizures and has led to Roger J. Porter of Bethesda. Dr. Dieter world-wide adoption (Gastaut, 1970). Schmidt of Berlin, and Dr. Gregory 0. Since the publication of the 1969 classifi- Walsh of Los Angeles attended as particication, objective and sophisticated methods pants and discussants in this workshop. for studying epileptic seizures have become In 1977, a workshop on generalized seicommonplace. These methods include zures was held in Berlin. The above Comvideo display of epileptic seizures on mag- mission members were present with the adnetic tape, the simultaneous recording of dition of Dr. Toyoji Wada of Shizuoka and the electroencephalogram using hard-wired invited participants who presented vidrecording techniques and radiotelemetry eotape data, including Dr. A. Cirignotta of with split screen display and instant replay Bologna, Dr. Peter Kellaway of Houston, capability. Dr. Cesare Lombroso of Boston, Dr. K. F. Since 1975, two further Commissions on Masuhr of Berlin, and Dr. D. Stefan of Classification and Terminology of the In- Bonn. The results of these workshops comternational League Against Epilepsy have prise the major portions of the version of convened in order to continue to update, the International Classification of Epileptic amend, and improve the classification in Seizures herewith proposed.

Proposal for Revised Clinical and ~lectro~nce~halo ~ra~hic Classification of Epileptic Seizures From the Commission on Classification and Terminology of the International League Against Epilepsy*

Objective To assess the risk of incident epilepsy among participants with prevalent dementia and the risk of incident dementia among participants with prevalent epilepsy in the Framingham Heart Study (FHS). Methods We analyzed prospectively collected data in the Original and Offspring FHS cohorts. To determine the risk of developing epilepsy among participants with dementia and the risk of developing dementia among participants with epilepsy, we used separate, nested, case–control designs and matched each case to 3 age-, sex- and FHS cohort–matched controls. We used Cox proportional hazards regression analysis, adjusting for sex and age. In secondary analysis, we investigated the role of education level and APOE e4 allele status in modifying the association between epilepsy and dementia. Results A total of 4,906 participants had information on epilepsy and dementia and dementia follow-up after age 65. Among 660 participants with dementia and 1,980 dementia-free controls, there were 58 incident epilepsy cases during follow-up. Analysis comparing epilepsy risk among dementia cases vs controls yielded a hazard ratio (HR) of 1.82 (95% confidence interval 1.05–3.16, p = 0.034). Among 43 participants with epilepsy and 129 epilepsy-free controls, there were 51 incident dementia cases. Analysis comparing dementia risk among epilepsy cases vs controls yielded a HR of 1.99 (1.11–3.57, p = 0.021). In this group, among participants with any post–high school education, prevalent epilepsy was associated with a nearly 5-fold risk for developing dementia (HR 4.67 [1.82–12.01], p = 0.001) compared to controls of the same educational attainment. Conclusions There is a bi-directional association between epilepsy and dementia. with either condition carrying a nearly 2-fold risk of developing the other when compared to controls.

Bi-directional association between epilepsy and dementia: The Framingham Heart Study

People with epilepsy — in particular, late-onset epilepsy of unknown aetiology — have an elevated risk of dementia, and seizures have been detected in the early stages of Alzheimer disease (AD), supporting the concept of an epileptic AD prodrome. However, the relationship between epilepsy and cognitive decline remains controversial, with substantial uncertainties about whether epilepsy drives cognitive decline or vice versa, and whether shared pathways underlie both conditions. Here, we review evidence that amyloid-β (Aβ) forms part of a shared pathway between epilepsy and cognitive decline, particularly in the context of AD. People with epilepsy show an increased burden of Aβ pathology in the brain, and Aβ-mediated epileptogenic alterations have been demonstrated in experimental studies, with evidence suggesting that Aβ pathology might already be pro-epileptogenic at the soluble stage, long before plaque deposition. We discuss the hypothesis that Aβ mediates — or is at least a major determinant of — a continuum spanning epilepsy and cognitive decline. Serial cognitive testing and assessment of Aβ levels might be worthwhile to stratify the risk of developing dementia in people with late-onset epilepsy. If seizures are a clinical harbinger of dementia, people with late-onset epilepsy could be an ideal group in which to implement preventive or therapeutic strategies to slow cognitive decline. People with epilepsy have an elevated risk of dementia, and seizures have been detected in the early stages of Alzheimer disease. Here, the authors review evidence that amyloid-β forms part of a shared pathway between epilepsy and cognitive decline.

Amyloid-β: a potential link between epilepsy and cognitive decline.

Objective To determine the risk of dementia after the development of late-onset epilepsy. Methods We used data from the Atherosclerosis Risk in Communities (ARIC) cohort study, which started in 1987 to 1989 with 15,792 mostly Black and White men and women from 4 US communities. We identified late-onset epilepsy (LOE; seizures starting at age 67 or later) from linked Medicare claims data. We used a Cox proportional hazards regression model to evaluate associations between LOE and dementia through 2017 as ascertained from neuropsychological testing, interviews, and hospital discharge surveillance, and we used multinomial logistic regression to assess the risk of dementia and mild cognitive impairment in the subset with full neuropsychological assessments available. We adjusted for demographics and vascular and Alzheimer disease risk factors. Results Of 9,033 ARIC participants with sufficient Medicare coverage data (4,980 [55.1%] female, 1993 [22.1%] Black), 671 met the definition of LOE. Two hundred seventy-nine (41.6%) participants with and 1,408 (16.8%) without LOE developed dementia (p Interpretation The risk of incident dementia is substantially elevated in individuals with LOE. Further work is needed to explore causes for the increased risk of dementia in this growing population.

Dementia in late-onset epilepsy: The Atherosclerosis Risk in Communities study.

Background/Objectives

Coexistent seizures add complexity to the burden of Alzheimer's disease (AD). We aim to estimate the incidence and prevalence of coexistent seizures and AD and summarize characteristics.



Design

A systematic review and meta‐analysis (PROSPERO protocol registration CRD42020150479).



Setting

Population‐, community‐, hospital‐, or nursing home‐based.



Participants and measurements

Thirty‐nine studies reporting on seizure incidence and prevalence in 21,198 and 380,777 participants with AD, respectively, and AD prevalence in 727,446 participants with seizures. When statistical heterogeneity and inconsistency (assessed by Q statistic and I2) were not shown, rates were synthesized using random effect.



Results

Studies were conducted in Australia, Brazil, Finland, France, Ireland, Italy, Japan, Netherlands, Portugal, Sweden, Taiwan, United Kingdom, and United States. The incidence of seizures among people with clinically diagnosed AD ranged from 4.2 to 31.5 per 1000 person‐years. Prevalence of seizures among people with clinically diagnosed AD ranged from 1.5% to 12.7% generally, but it rose to the highest (49.5% of those with early‐onset AD) in one study. Meta‐analysis reported a combined seizure prevalence rate among people with pathologically verified AD at 16% (95% confidence interval [CI] 14–19). Prevalence of seizure in autosomal dominant AD (ADAD) ranged from 2.8% to 41.7%. Being younger was associated with higher risk of seizure occurrence. Eleven percent of people with adult‐onset seizures had AD (95%CI, 7‐14).



Conclusion

Seizures are common in those with AD, and seizure monitoring may be particularly important for younger adults and those with ADAD.

Systematic review of coexistent epileptic seizures and Alzheimer's disease: Incidence and prevalence.

Incidence of dementia in patients with adult-onset epilepsy of unknown causes.

Abstract Non-motor symptoms (NMS) are common among patients with Parkinson’s disease and reduce patients’ quality of life (QOL). However, there remain considerable unmet needs for NMS management. Three monoamine oxidase B inhibitors (MAO-BIs), selegiline, rasagiline, and safinamide, have become commercially available in many countries. Although an increasing number of studies have reported potential beneficial effects of MAO-BIs on QOL and NMS, there has been no consensus. Thus, the primary objective of this study was to provide an up-to-date systematic review of the QOL and NMS outcomes from the available clinical studies of MAO-BIs. We conducted a literature search using the PubMed, Scopus, and Cochrane Library databases in November 2021. We identified 60 publications relevant to this topic. Overall, rasagiline and safinamide had more published evidence on QOL and NMS changes compared with selegiline. This was likely impacted by selegiline being introduced many years prior to the field embarking on the study of NMS. The impact of MAO-BIs on QOL was inconsistent across studies, and this was unlikely to be clinically meaningful. MAO-BIs may potentially improve depression, sleep disturbances, and pain. In contrast, cognitive and olfactory dysfunctions are likely unresponsive to MAO-BIs. Given the paucity of evidence and controlled, long-term studies, the effects of MAO-BIs on fatigue, autonomic dysfunctions, apathy, and ICD remain unclear. The effects of MAO-BIs on static and fluctuating NMS have never been investigated systematically. More high-quality studies will be needed and should enable clinicians to provide personalized medicine based on a non-motor symptom profile. 

https://www.nature.com/articles/s41531-022-00339-2.pdf

Effects of MAO-B inhibitors on non-motor symptoms and quality of life in Parkinson’s disease: A systematic review

Dynamic nuclear polarization (DNP) is a cutting-edge technique that markedly enhances the detection sensitivity of molecules using nuclear magnetic resonance (NMR)/magnetic resonance imaging (MRI). This methodology enables real-time imaging of dynamic metabolic status in vivo using MRI. To expand the targetable metabolic reactions, there is a demand for developing exogenous, i.e., artificially designed, DNP-NMR molecular probes; however, complying with the requirements of practical DNP-NMR molecular probes is challenging because of the lack of established design guidelines. Here, we report Ala-[1-13C]Gly-d2-NMe2 as a DNP-NMR molecular probe for in vivo detection of aminopeptidase N activity. We developed this probe rationally through precise structural investigation, calculation, biochemical assessment, and advanced molecular design to achieve rapid and detectable responses to enzyme activity in vivo. With the fabricated probe, we successfully detected enzymatic activity in vivo. This report presents a comprehensive approach for the development of artificially derived, practical DNP-NMR molecular probes through structure-guided molecular design.

Structure-guided design enables development of a hyperpolarized molecular probe for the detection of aminopeptidase N activity in vivo

/pdf/effects-of-mao-b-inhibitors-on-non-motor-symptoms-and-3mn7nhpr.pdf

Cryogenic electron microscopy is one of the fastest and most robust methods for capturing high-resolution images of proteins, but stringent sample preparation, imaging conditions, and in situ radiation damage inflicted during data acquisition directly affect the resolution and ability to capture dynamic details, thereby limiting its broader utilization and adoption for protein studies. We addressed these drawbacks by introducing synthesized giant carbon nano-test tubes (GCNTTs) as radiation-insulating materials that lessen the irradiation impact on the protein during data acquisition, physical molecular concentrators that localize the proteins within a nanoscale field of view, and vessels that create a microenvironment for solution-phase imaging. High-resolution electron microscopy images of single and aggregated hemoglobin molecules within GCNTTs in both solid and solution states were acquired. Subsequent scanning transmission electron microscopy, small-angle neutron scattering, and fluorescence studies demonstrated that the GCNTT vessel protected the hemoglobin molecules from electron irradiation-, light-, or heat-induced denaturation. To demonstrate the robustness of GCNTT as an imaging platform that could potentially augment the study of proteins, we demonstrated the robustness of the GCNTT technique to image an alternative protein, d-fructose dehydrogenase, after cyclic voltammetry experiments to review encapsulation and binding insights. Given the simplicity of the material synthesis, sample preparation, and imaging technique, GCNTT is a promising imaging companion for high-resolution, single, and dynamic protein studies under electron microscopy.

Keita Hiraga

Papers

Incidence of dementia in patients with adult-onset epilepsy of unknown causes.

Effects of MAO-B inhibitors on non-motor symptoms and quality of life in Parkinson’s disease: A systematic review

Structure-guided design enables development of a hyperpolarized molecular probe for the detection of aminopeptidase N activity in vivo

Effects of MAO-B inhibitors on non-motor symptoms and quality of life in Parkinson’s disease: A systematic review

Giant Carbon Nano-Test Tubes as Versatile Imaging Vessels for High-Resolution and In Situ Observation of Proteins.