Faculty Bibliography

Childhood adversity is increasingly recognized as a critical modifier of neurologic disorder development and disease severity, including in the neuroimmune disorder multiple sclerosis (MS). While previous studies have linked early-life adversity to increased MS susceptibility and more severe disease, the underlying biological mechanisms remain poorly understood. This study investigated associations between childhood adversity and MS clinical features, with a focus on two potential pathogenic mechanisms: allostatic load and epigenetic modifications. We evaluated 60 consecutively enrolled young adults with MS; 30 with paediatric-onset MS (POMS) and 30 with adult-onset MS (AOMS). At time of enrolment in this cross-sectional study, participants had MS disease duration of 6 years on average. POMS participants were mean 22.09 (2.66) years and AOMS participants were mean 32.41 (2.19) years old. 62% of participants were female. Childhood adversity was defined using a composite index of individual, family and socioeconomic measures captured by the adverse childhood experiences questionnaire, parental education level and estimated household income during childhood. Clinical outcomes included patient-reported SymptoMScreen questionnaire regarding MS symptom burden and MS neurologist-assessed disability using the Expanded Disability Status Scale (EDSS) of the participant's neurologic exam at the time of enrolment. Circulating biomarkers of allostatic load and genome-wide epigenetic profiles (DNA methylation via RRBS; reduced representation bisulfite sequencing) were also assessed. A history of high childhood adversity was associated with significantly greater patient-reported MS symptom burden (P = 0.001) and higher neurologist-reported EDSS disability scores (P = 0.028), independent of disease duration or timing of treatment initiation. There were no differences between childhood adversity and circulating biomarkers of allostatic load. While childhood adversity was not associated with global epigenetic changes across the entire cohort, stratified analysis revealed divergent methylation patterns by age of MS onset: POMS participants with childhood adversity had increased DNA methylation, whereas AOMS participants with childhood adversity showed decreased methylation compared to individuals without childhood adversity. None of the observed clinical and biologic differences were explained by differences in disease duration or the interval between symptom onset and treatment initiation. Our findings suggest that childhood adversity is associated with increased MS symptom burden and neurologic disability in young adults with MS. Childhood adversity may differentially shape the epigenome, depending on the age of MS onset, with potential implications for disease trajectory and therapeutic vulnerability. These results support the biological embedding of childhood adversity in MS and highlight the need for age- and exposure-sensitive approaches to understanding MS pathogenesis across the lifespan.

OBJECTIVE:To compare seizure outcomes during pregnancy in women with epilepsy (WWE) by history of catamenial patterns. BACKGROUND:Catamenial patterns are defined as increased seizure frequency during certain phases of the menstrual cycle (perimenstrual, peri-ovulatory, or luteal in anovulatory cycles). Animal studies suggest seizure improvement occurs with higher progesterone and allopregnanolone concentrations and lower estrogen concentrations. Prior human studies also reported that WWE with catamenial patterns were more likely to have improved seizure frequency during pregnancy, presumably due to higher sensitivity to fluctuations in sex steroid hormones. DESIGN/METHODS/METHODS:Women with epilepsy (WWE), ages 18-40yo, were enrolled in a longitudinal, prospective cohort study at time of attempting conception to compare fertility outcomes to healthy controls. Once enrolled, WWE used a daily diary app for menstrual and seizure tracking from preconception through delivery. For this secondary analysis, participants were excluded if they chose to discontinue the study, if they did not become pregnant, were seizure free preconception, if their diary data was inadequate (defined as <80 % of the days tracked), or if they had <1 month of seizure data tracked prior to conception. Prospective diary data was used to determine if participants met criteria for observed catamenial patterns. Seizure frequency during pregnancy was compared to preconception frequency. RESULTS:Among 89 participants, 13 became pregnant with seizure tracking; 6 (46 %) met criteria for catamenial epilepsy. Focal epilepsy was less common than generalized epilepsy in the catamenial group (33 %) vs the non-catamenial group (86 %, p = 0.10). No significant differences in seizure frequency change from preconception to pregnancy were observed between groups (p = 0.42). During pregnancy, 33 % of the catamenial group and 43 % of the non-catamenial group became seizure-free (p = 0.99). Seizure improvement or stability occurred in 67 % and 86 %, respectively (p = 0.56). CONCLUSIONS:In patients who had preconception seizures, seizure control during pregnancy was generally favorable: many patients' seizure frequency improved or achieved seizure freedom. There was no clear evidence that a pre-conception catamenial pattern immediately before pregnancy altered prognosis. Further research is needed to guide counseling and treatment during pregnancy.

OBJECTIVE:To determine the test performance of cutaneous phosphorylated alpha-synuclein (P-SYN) in dementia with Lewy bodies (DLB), individuals with reduced Montreal Cognitive Assessment (MoCA) and healthy controls. METHODS:This is the first subgroup analysis of the Synuclein-One study, a prospective, blinded study evaluating P-SYN detection from skin biopsies in 218 subjects with a referral diagnosis of control (N = 151) and DLB (N = 67). All subjects completed detailed examinations, questionnaires, and had skin biopsies for detection of P-SYN. DLB patients were included if meeting the 4th DLB consensus probable criteria. Control subjects, aged 40-99, had no history, examination findings, or symptoms suggestive of a synucleinopathy or neurodegenerative disease. An expert review panel, blinded to pathological data, determined the final diagnosis. Controls with reduced MoCA (MoCA < 26, N = 26) at screening were analyzed separately. RESULTS:After expert panel review, only 50/67 patients met consensus criteria for DLB, 26/151 controls had a reduced MoCA, and 120/151 controls had a normal MoCA. The proportions of subjects with cutaneous P-SYN detected by skin biopsy were 96.0% (48 of 50) of the DLB group, 31% (8 of 26) of the controls with reduced MoCA, and 3.3% (4 of 120) of the controls with normal MoCA. INTERPRETATION/CONCLUSIONS:In this prospective, blinded, cross-sectional study, a high proportion of subjects meeting clinical consensus criteria for DLB had P-SYN detected in skin biopsies. Almost 1/3 of subjects with reduced MoCA testing also had P-SYN detected. These results support a role for skin biopsy detection of P-SYN in patients with DLB. TRIAL REGISTRATION/BACKGROUND:NCT04700722.

OBJECTIVE:The latest European Medicines Agency (EMA) guideline on the clinical investigation of medicines to treat epileptic disorders was adopted by the EMA Committee for Medicinal Products for Human Use in 2025. We compared this guideline with the previous version (2010), highlighting areas where significant revisions were introduced. METHODS:The 2025 and 2010 versions of the guideline were systematically analyzed to identify significant modifications. RESULTS:The latest EMA guideline incorporated terminology from the 2017 International League Against Epilepsy (ILAE) classification of seizures and epilepsy and the 2022 classification of syndromes and replaced the older term "antiepileptic drug (AED)" with "antiseizure medication (ASM)." Recommendations for add-on studies in common epilepsies have remained substantially unchanged, the main revision being the acceptability of the time-to-event design also for confirmatory trials, provided it is not the only design in the clinical development plan. A major novelty is the feasibility of extrapolating data from add-on trials to the monotherapy indication, provided specific conditions are met. Guidance on pediatric ASM development has been expanded, addressing extrapolation of efficacy from data in adults and older children and options for studies in developmental and epileptic encephalopathies and other rare epilepsies. Compared with the previous guideline, greater emphasis is placed on nonseizure outcomes, including functional, quality of life, and patient-reported outcomes. Two new sections have been introduced, addressing studies in neonates and clinical trials in status epilepticus and other seizure emergencies. Options for innovative designs, including registry-based studies, are also discussed in situations where randomized controlled trials are unfeasible. SIGNIFICANCE/CONCLUSIONS:The updated guideline reflects the changing scenario in epilepsy treatment development, with a greater focus on pediatric epilepsies, rare epilepsies, and other indications with high unmet needs. The updates also reflect the contribution during the consultation process by a wide range of stakeholders, including the ILAE Task Force on Regulatory Affairs.

OBJECTIVES/OBJECTIVE:To explore the evolution of the grief experience following Sudden Unexpected Death in Epilepsy (SUDEP) and identify factors that assist the bereaved in coping with their loss. METHODS:A survey formulated by a multidisciplinary team gathered information gathered information on decedent and respondent demographics, epilepsy details, circumstances surrounding death, postmortem experiences, descriptions of grief overtime (from 3 months to > 10 years post death), insights into coping strategies and recommendations for assisting the bereaved. RESULTS:A total of 206 participants completed the survey (predominantly middle-aged white females who were parents of the deceased). Most respondents (69.2 %) were unaware of SUDEP prior to the death and strongly desired to have had prior information. Negative impacts on relationships and mental health were highest at three months post-loss but gradually improved over time; feelings of sadness persisted while anger and guilt decreased, and acceptance increased. Interactions with understanding peers, supportive family or friends, and professional counseling were identified as most helpful, alongside clear communication and support from medical professionals and advocacy groups. CONCLUSIONS:This study highlights the profound and evolving nature of grief following SUDEP, describes the importance of SUDEP disclosure as part of comprehensive epilepsy care, and illustrates the need for ongoing and dynamic support for the bereaved. Interpretation of the findings is limited as the respondents were predominantly middle-aged white females who were parents of the deceased.

Obstructive Sleep Apnea (OSA) is an extremely prevalent disorder and mostly underdiagnosed. Its prevalence is even higher among African Americans (AA), Hispanic, Asian Americans and Native Americans (NA) adults and children. AA present younger, with more severe and comorbid OSA, and are sleepier than their white counterparts. Evidence suggests this problem could be as severe in Hispanics, Asian Americans and NA. This first part of the review will focus on epidemiology and data in the adult population.

Peptidoglycan (PG), the primary load-bearing component of bacterial cell envelopes, is a bio-derived material whose mechanical and hydration properties are central to microbial viability and their environmental responsiveness. PG has been increasingly recognized as a scalable water-responsive (WR) material, capable of converting chemical potential gradients from ambient changes in relative humidity (RH) directly into mechanical work. In this study, we leverage stress-induced PG remodeling pathways in a BB-3 Escherichia coli (E. coli) strain to modulate the architecture of its PG sacculus for enhanced WR performance. Under arabinose-deprived conditions (-Ara), BB-3 PG exhibits a twofold increase in the ratio of crosslinked-to-linear muropeptide stems and a threefold rise in the relative abundance of ③-③ (mDap-mDap) linkages relative to an arabinose-rich (+Ara) control. When responding to RH changes between 10% and 90% RH, these molecular-level modifications translated into a fivefold increase in WR actuation energy density (623.0 kJ/m³) with rapid response times on the order of seconds (τ_d: 1.8 s, τ_h: 0.7 s). The remodeled PG also displays a significant increase in stiffness (E: 8.9 GPa at 10% RH) and an 8% greater uptake of water, driving the PG matrix to generate twofold higher WR strain (ε: 30.2%). The observed increases in water retention and WR behavior of E. coli PG may also carry intriguing evolutionary implications, reflecting adaptive strategies microbes take to restructure PG layers and survive under microenvironmental nutrient scarcity. STATEMENT OF SIGNIFICANCE: Current testing of water responsive (WR) engineered living materials (ELMs) has largely overlooked bacterial species other than Bacillus subtilis. Our work addresses this gap by demonstrating that the peptidoglycan (PG) sacculus of Escherichia coli also exhibits robust WR properties. Through leveraging a combination of genetic and environmental factors during the organism's growth phase, we demonstrate that these properties can be rationally improved to yield enhanced actuator materials. By establishing a connection between PG crosslinking architecture and emergent mechanical and hydration dynamics, we present a promising approach to engineer dynamic and sustainable ELMs that can be employed as active components in high-performance actuators.