Faculty Bibliography

Stem cell therapies are progressively redefining the treatment landscape for a spectrum of neurological and age-related disorders. This review discusses the molecular and functional attributes of stem cells, emphasizing the roles of neural stem cells and mesenchymal stem cells in the context of neurological diseases such as stroke, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, Parkinson's disease, and Alzheimer's disease. The review also explores the potential of stem cells in addressing the aging process. The paper analyzes stem cells' intrinsic properties of self-renewal, differentiation, and paracrine effects, alongside the importance of laboratory-modified stem cells like induced pluripotent stem cells and transgenic stem cells. Insights into disease-specific stem cell treatments are offered, reviewing both successes and challenges in the field. This includes the translational difficulties from rodent studies to human trials. The review concludes by acknowledging the uncharted territories that warrant further investigation, emphasizing the potential roles of stem cell-derived exosomes and indole-related molecules, and aiming at providing a basic understanding of stem cell therapies.

OBJECTIVE/UNASSIGNED:A pilot study to preliminarily examine the effects of Prism EFP NeuroFeedback (NF) in adult ADHD. METHOD/UNASSIGNED:Prism EFP NF is a form of NF specifically designed to target emotional dysregulation (ED) through down regulation of amygdala activity. Prism EFP NF has been shown to improve other disorders with significant ED. Nine participants with adult ADHD received an open trial of Prism EFP NF consisting of fifteen sessions over 8 weeks; all completed at least 5 weeks of treatment with seven completing all 8 weeks. Outcomes were assessed by change in ADHD symptoms from baseline to End of Treatment. RESULTS/UNASSIGNED:About two-third reduction was seen in total DSM ADHD symptom scores (primary outcome measure) with improvement observed in all other clinical measures. No significant adverse events were seen. CONCLUSION/UNASSIGNED:This preliminary trial found substantial effects of Prism EFP NF on ADHD/ED symptoms and global impairment.

Migraine is a leading cause of disability worldwide. A minority of individuals with migraine develop resistant or refractory conditions characterised by ≥ 8 monthly days of debilitating headaches and inadequate response, intolerance, or contraindication to ≥3 or all preventive drug classes, respectively. Resistant and refractory migraine are emerging clinical definitions stemming from better knowledge of the pathophysiology of migraine and from the advent of migraine-specific preventive treatments. Resistant migraine mostly results from drug failures, while refractory migraine has complex and still unknown mechanisms that impair the efficacy of preventive treatments. Individuals with resistant migraine can be treated with migraine-specific preventive drugs. The management of refractory migraine is challenging and often unsuccessful, being based on combinations of different drugs and non-pharmacological treatment. Future research should aim to identify individuals at risk of developing treatment failures, prevent the condition, investigate the mechanisms of refractoriness to treatments, and find effective treatment strategies.

Correlating the structure and dynamics of proteins with biological function is critical to understanding normal and dysfunctional cellular mechanisms. We describe a quantitative method of hydroxyl radical generation via Fe(II)-ethylenediaminetetraacetic acid (EDTA)-catalyzed Fenton chemistry that provides ready access to protein oxidative footprinting using equipment commonly found in research and process control laboratories. Robust and reproducible dose-dependent oxidation of protein samples is observed and quantitated by mass spectrometry with as fine a single residue resolution. An oxidation analysis of lysozyme provides a readily accessible benchmark for our method. The efficacy of our oxidation method is demonstrated by mapping the interface of a RAS-monobody complex, the surface of the NIST mAb, and the interface between PRC2 complex components. These studies are executed using standard laboratory tools and a few pennies of reagents; the mass spectrometry analysis can be streamlined to map the protein structure with single amino acid residue resolution.

BACKGROUND:Patient-reported outcomes (PRO) are increasingly utilized as part of the routine clinical assessment in people with multiple sclerosis (pwMS). The long-term effect of disease modifying therapies (DMTs) and their discontinuation on PRO measures remains largely unknown. METHODS:Two pwMS groups treated with natalizumab were selected from the New York State MS Consortium (NYSMSC) database. The first group utilized long-term follow-up data of pwMS that either still continue natalizumab treatment or discontinued. Minimal requirement of three visits (before natalizumab initiation, during treatment and after discontinuation/latest follow-up) was implemented. The second group consisted of pwMS that completed PRO questionnaire on the day of the infusion and 7 days later PROs were assessed using the LIFEware System™ that assesses limitations in multiple physical and psychosocial domains. Additional physical disability was assessed using Expanded Disability Status Scale (EDSS) and Timed 25-ft walk test (T25FWT). PRO reports were Rasch-transformed, ranging from 0 to 100, with higher scores indicating a better outcome. Linear mixed-effect models and paired analyses were utilized. RESULTS:Within the prospective cohort, 242 pwMS were followed on average of 6.5 years. Greater number of PRO domains worsened in the 141 pwMS that discontinued natalizumab when compared to 101 pwMS that remained on the drug (10 vs. 2 PRO domains). PwMS that discontinued natalizumab had significant decline in PROs regarding lower extremities, bladder and bower control and psychosocial aspects (feeling lonesome). Contrarily, pwMS that continued natalizumab had significant improvement in bladder and bowel PRO measures. Seven days after the natalizumab infusion, the 67 pwMS from the prospective cohort reported improvement in PRO measures of fatigue (62.8 vs. 66.4, p = 0.019), bladder limitations (80.3 vs. 85.0, p = 0.012), and feelings of lonesomeness (81.2 vs. 88.0, p = 0.009). CONCLUSION/CONCLUSIONS:Continuous natalizumab treatment provides long-term stability or improvement in PRO measures. Natalizumab also provides short term improvements recorded after the infusion.

BACKGROUND AND OBJECTIVES/OBJECTIVE:The purpose of this guideline is to update the 2010 American Academy of Neurology (AAN) brain death/death by neurologic criteria (BD/DNC) guideline for adults and the 2011 American Academy of Pediatrics, Child Neurology Society, and Society of Critical Care Medicine guideline for infants and children and to clarify the BD/DNC determination process by integrating guidance for adults and children into a single guideline. Updates in this guideline include guidance related to conducting the BD/DNC evaluation in the context of extracorporeal membrane oxygenation, targeted temperature management, and primary infratentorial injury. METHODS:A panel of experts from multiple medical societies developed BD/DNC recommendations. Because of the lack of high-quality evidence on the subject, a novel, evidence-informed formal consensus process was used. This process relied on the panel experts' review and detailed knowledge of the literature surrounding BD/DNC to guide the development of preliminary recommendations. Recommendations were formulated and voted on, using a modified Delphi process, according to the 2017 AAN Clinical Practice Guideline Process Manual. MAJOR RECOMMENDATIONS/CONCLUSIONS:Eighty-five recommendations were developed on the following: (1) general principles for the BD/DNC evaluation, (2) qualifications to perform BD/DNC evaluations, (3) prerequisites for BD/DNC determination, (4) components of the BD/DNC neurologic examination, (5) apnea testing as part of the BD/DNC evaluation, (6) ancillary testing as part of the BD/DNC evaluation, and (7) special considerations for BD/DNC determination.

BACKGROUND:Our previous study identified a significant association between lower time spent outdoors, as a proxy of sun exposure, and a higher risk of pediatric-onset multiple sclerosis (POMS). UV radiation modulates the expression of several genes, but it is unknown whether these genes modify the effect of sun exposure on POMS risk. METHODS:In an age- and sex-matched case-control study, we evaluated the additive and multiplicative interactions between time spent outdoors and genetic non-HLA risk variants for developing POMS within the metabolic pathways of UV radiation, including CD28(rs6435203), CD86(rs9282641), and NFkB1(rs7665090) and the top two HLA risk factors (presence of DRB1×15 and absence of A*02). RESULTS:In an adjusted model (332 POMS cases, 534 healthy controls), greater time compared to <30 min/day spent outdoors during the prior summer and higher UV radiation dose were associated with decreased odds of POMS (OR 0.66, 95% CI 0.56-0.78, p < 0.001; OR 0.78, 95 % CI 0.62-0.98, p = 0.04, respectively). No significant additive or multiplicative interactions were found between risk factors. CONCLUSIONS:The exploration of gene-environment interactions in the risk of developing MS can unravel the underlying mechanisms involved. Although we do not have evidence that our candidate genes contribute to interactions, other genes may.