Neurological Disorders And Stroke Research Articles

Study protocol: Cerebral autoregulation, brain perfusion, and neurocognitive outcomes after traumatic brain injury -CAPCOG-TBI.

Moderate-severe traumatic brain injury (msTBI) stands as a prominent etiology of adult disability, with increased risk for cognitive impairment and dementia. Although some recovery often occurs within the first year post-injury, predicting long-term cognitive outcomes remains challenging, partly due to the significant pathophysiological heterogeneity of TBI, including acute cerebrovascular injury. The primary aim of our recently funded study, cerebral autoregulation, brain perfusion, and neurocognitive outcomes after traumatic brain injury (CAPCOG-TBI), is to determine if acute cerebrovascular dysfunction after msTBI measured using multimodal non-invasive neuromonitoring is associated with cognitive outcome at 1-year post-injury. This longitudinal observational study will be conducted at two Level 1 trauma centers in Texas, USA, and will include adult patients with msTBI, and/or mild TBI with neuroimaging abnormalities. Multimodal cerebral vascular assessment using transcranial Doppler and cerebral near-infrared spectroscopy (NIRS) will be conducted within 7-days of onset of TBI. Longitudinal outcomes, including cognitive/functional assessments (Glasgow Outcome Scale and Patient-Reported Outcomes Measurement Information System), cerebral vascular assessment, and imaging will be performed at follow-ups 3-, 6-, and 12-months post-injury. We aim to recruit 100 subjects with msTBI along with 30 orthopedic trauma controls (OTC). This study is funded by National Institute of Neurological Disease and Stroke (NINDS) and is registered on Clinicaltrial.org (NCT06480838). We anticipate that msTBI patients will exhibit impaired cerebrovascular function in the acute phase compared to the OTC group. The severity of cerebrovascular dysfunction during this stage is expected to inversely correlate with cognitive and functional outcomes at 1-year post-injury. Additionally, recovery from cerebrovascular dysfunction is expected to be linked to cognitive recovery. The results of this study could help to understand the contribution of cerebrovascular dysfunction to cognitive outcomes after TBI and pave the way for innovative vascular-focused interventions aimed at enhancing cognitive recovery and mitigating neurodegeneration following msTB. In addition, its focus toward personalized medicine to aid in the management and prognosis of TBI patients.

Correlation of Clinical and Electrophysiological Criteria in the Diagnosis of Guillain-Barré Syndrome: A Prospective Observational Study.

There are many criteria for diagnosing Guillain-Barré syndrome (GBS), and the yield of these diagnostic criteria varies. Each criterion requires some laboratory data and nerve conduction studies (NCS). Although supportive laboratory data are reassuring when present in suspected cases of GBS, when absent, they can potentially cause further delay in diagnosis and treatment. There is no gold standard test for the diagnosis of GBS, and there are multiple diagnostic criteria for GBS to date. The aim of the study is to know the sensitivity of different criteria, clinical and electrophysiological, for the diagnosis of GBS and to study the clinical spectrum and electrophysiological spectrum of GBS in our cohort of patients. We studied a total of 43 cases who presented with one or more of the following symptoms: relatively symmetrical and progressive flail-type weakness of more than one limb, with or without ataxia and/or ophthalmoplegia, and were diagnosed with GBS according to clinical criteria at the time of admission to Government Stanley Medical College Hospital. GBS mimics were ruled out. In all patients, the demographic data, cerebrospinal fluid (CSF) analysis (if done), and electrophysiological findings fitting into the diagnostic criteria of National Institute of Neurological Disorders and Stroke (NINDS), Dutch, and Brighton criteria were recorded. The need for assisted mechanical ventilation, neurology intensive care unit (NICU) stay, any complications, and treatment outcome details were recorded in a structured proforma. Most of the patients in our study were in their fourth decade of life, with a mean age of 41.37 years, similar to previous studies from India. Men are more frequently affected compared to women, similar to what has been observed in most studies done previously worldwide. In our study, electrophysiological criteria by Dutch criteria (87.5%), Brighton criteria (87.5%), and NINDS criteria (85.6%) had low sensitivity compared to the clinical criteria. In the present study, electrophysiological criteria proposed by the NINDS, Dutch, and Brighton criteria are less sensitive compared to clinical criteria in diagnosing GBS at early stages. Clinical criteria alone may be useful in resource-poor countries and at peripheral healthcare systems where NCS are not always readily available.

Base rates of healthy community-dwelling adults meeting criteria for traumatic encephalopathy syndrome and levels of chronic traumatic encephalopathy certainty

Objective: The National Institute of Neurological Disorders and Stroke (NINDS) recently revised criteria for Traumatic Encephalopathy Syndrome (TES) (Katz et al.), aiming to improve the specificity of former TES criteria (Montenigro et al.) and adding methods to gauge certainty of underlying Chronic Traumatic Encephalopathy (CTE). This study examined base rates of Montenigro et al. and Katz et al. TES criteria in healthy community-dwelling adults. Method: Participants consisted of healthy adults (n = 835; M = 48.1 ± 18.2 years-old, range = 18–85; 37.1% male; 64.1% White) without known history of neurotrauma or psychiatric or neurological conditions. The former and current TES criteria were operationalized using the NIH Toolbox Cognition, Motor, and Emotion batteries and PROMIS-29. Results: Per Katz et al. criteria, 36.9% had symptoms Suggestive of CTE (i.e. either cognitive impairment or neurobehavioral dysregulation), 4.1% had Possible CTE (i.e. requiring cognitive impairment and two additional criteria), and 0.8% had Probable CTE (i.e. requiring cognitive impairment and three additional criteria). The requirement of cognitive impairment for Possible CTE certainty decreased the base rate of Possible CTE tenfold from Montenigro et al. criteria (40.1%). Conclusion: The Katz et al. criteria were met less frequently by healthy adults than the Montenigro et al. criteria. Requiring cognitive impairment and more supportive TES features when gauging CTE certainty may reduce false-positive diagnoses. This finding supports the role of neuropsychologists in the diagnosis and monitoring of patients in TES research studies. To assess specificity, future research should examine base rates of Katz et al. criteria in other psychiatric and neurological conditions.

The Neuroscience Research Opportunities to Increase Diversity Program: Transformative and Successful Research Training Strategies for Undergraduate Students within Hispanic Serving Institutions.

Over the past 14 years, the Neuroscience Research Opportunities to Increase Diversity (NeuroID) program, funded by the National Institute of Neurological Diseases and Stroke (NINDS), has played a transformative role in training numerous undergraduate Hispanic students within The University of Puerto Rico-Rio Piedras (UPR-RP). This innovative Neuroscience-based research training initiative has successfully guided dozens of Hispanic students toward graduate programs in Neuroscience, significantly contributing to the enhancement of diversity within the academic and scientific fields. The achievements of the NeuroID program can be attributed to three key objectives. Firstly, the establishment of a comprehensive and innovative program has provided Hispanic undergraduate students with invaluable insights into various facets of a research career in neuroscience. Secondly, the program has fostered a robust mentorship network that supports selected students throughout their journey to become neuroscientists. Thirdly, it has strengthened the neuroscience network in Puerto Rico by bridging the gap between undergraduate teaching universities and research laboratories in top-tier institutions across the mainland United States.

Common Data Elements for Disorders of Consciousness: Recommendations from the Working Group on Outcomes and Endpoints.

Clinical management of persons with disorders of consciousness (DoC) is dedicated largely to optimizing recovery. However, selecting a measure to evaluate the extent of recovery is challenging because few measures are designed to precisely assess the full range of potential outcomes, from prolonged DoC to return of preinjury functioning. Measures that are designed specifically to assess persons with DoC are often performance-based and only validated for in-person use. Moreover, there are no published recommendations addressing which outcome measures should be used to evaluate DoC recovery. The resulting inconsistency in the measures selected by individual investigators to assess outcome prevents comparison of results across DoC studies. The National Institute of Neurological Disorders and Stroke (NINDS) common data elements (CDEs) is an amalgamation of standardized variables and tools that are recommended for use in studies of neurologic diseases and injuries. The Neurocritical Care Society Curing Coma Campaign launched an initiative to develop CDEs specifically for DoC and invited our group to recommend CDE outcomes and endpoints for persons with DoCs. The Curing Coma Campaign Outcomes and Endpoints CDE Workgroup, consisting of experts in adult and pediatric neurocritical care, neurology, and neuroscience, used a previously established five-step process to identify and select candidate CDEs: (1) review of existing NINDS CDEs, (2) nomination and systematic vetting of new CDEs, (3) CDE classification, (4) iterative review and approval of panel recommendations, and (5) development of case report forms. Among hundreds of existing NINDS outcome and endpoint CDE measures, we identified 20 for adults and 18 for children that can be used to assess the full range of recovery from coma. We also proposed 14 new outcome and endpointCDE measures for adults and 5 for children. The DoC outcome and endpoint CDEs are a starting point in the broader effort to standardize outcome evaluation of persons with DoC. The ultimate goal is to harmonize DoC studies and allow for more precise assessment of outcomes after severe brain injury or illness. An iterative approach is required to modify and adjust these outcome and endpoint CDEs as new evidence emerges.

An Approach to Successful Development of Clinician-Scientists in Neurology: The NINDS R25 Experience.

Training clinician-scientists is a primary objective of many academic neurology departments, as these individuals are uniquely positioned to perform insightful clinical or laboratory-based research informed both by clinical knowledge and their own experiences caring for patients. Despite its importance, training clinician-scientists has perhaps never been so challenging. The National Institute of Neurologic Disorders and Stroke (NINDS) R25 program was designed in an attempt to support these individuals, decrease the time needed to obtain National Institutes of Health K awards, and to help educate a cohort of trainees preparing for a career in academic neurology. We endeavored to describe the structure and features of the program while examining its outcomes. R25 outcome data from 2009 to 2024 were reviewed. Statistical comparisons were made using 2-sided Mann-Whitney U testing. A total of 67% of adult neurologists who received an R25 had a successful application for a National Institutes of Health K award compared with 45% of adult neurologists who had not received R25 support (p < 0.0001). Among child neurologists, 73% who applied went on to receive K funding after R25 support, compared with 45% who had not been part of the R25 program (p < 0.001). The average time between completion of residency and obtaining a K award for R25 participants was decreased by 26 months among those with an MD/PhD degree, and 32 months for those with an MD degree compared with non-R25 individuals. The R25 program has been successful in achieving its training goals, but stands as only one component of support for aspiring clinician-scientists. Investments and commitments made by academic neurology departments are key to supporting this success. ANN NEUROL 2024.

Cervical spinal cord morphometrics in degenerative cervical myelopathy: quantification using semi-automated normalized technique and correlation with neurological dysfunctions

Degenerative cervical myelopathy (DCM) is characterized by spinal cord atrophy. Accurate estimation of spinal cord atrophy is key to the understanding of neurological diseases, including DCM. However, its clinical application is hampered by difficulties in its precise and consistent estimation due to significant variability in spinal cord morphometry along the cervical spine, both within and between individuals. To characterize morphometrics of the compressed spinal cord in DCM patients. We employed our semiautomated analysis framework that incorporates the Spinal Cord Toolbox (SCT) and a normalization approach to effectively address the challenges posed by cord compression in these patients. Additionally, we examined the clinical relevance of these morphometric measures to enhance our understanding of DCM pathophysiology. Prospective study. This study investigated 36 DCM patients and 31 healthy controls (HCs). Clinical scores including 9-hole peg test for hand dexterity, hand grip strength, balance, gait speed, modified Japanese Orthopaedic Association (mJOA) score, and imaging-based spinal cord morphometrics. Using the generic spine acquisition protocol and our semiautomated analysis pipeline, spinal cord morphometrics, including cross-sectional area (CSA), anterior-posterior (AP) and transverse (RL) diameters, eccentricity, and solidity, were estimated from sagittal T2w magnetic resonance imaging (MRI) images using the Spinal Cord Toolbox (SCT). Normalized metrics were extracted from the C1 to C7 vertebral levels and compared between DCM patients and HC. Morphometric data at regions of maximum spinal cord compression (MSCC) were correlated with the clinical scores. A subset of participants underwent follow-up scans at 6 months to monitor longitudinal changes in spinal cord atrophy. Spinal cord morphometric data were normalized against the healthy population morphometry (PAM50 database) and extracted for all participants. DCM patients showed a notable reduction in CSA, AP, and RL diameter across all vertebral levels compared to HC. MSCC metrics correlated significantly with clinical scores like dexterity, grip strength, and mJOA scores. Longitudinal analysis indicated a decrease in CSA and worsening clinical scores in DCM patients. Our processing pipeline offers a reliable method for assessing spinal cord compression in DCM patients. Normalized spinal cord morphometrics, particularly the CSA could have potential for monitoring DCM disease severity and progression, guiding treatment decisions. Furthermore, to our knowledge our study is the first to apply the generic spinal cord acquisition protocol, ensuring consistent imaging across different MRI scanners and settings. Coupled with our semiautomated analysis pipeline, this protocol is key for the detailed morphometric characterization of compressed spinal cords in patients with DCM, a disease that is both complex and heterogenous. This study was funded by the National Institute of Neurological Disorders and Stroke (NINDS) (K23:NS091430) and (R01: NS129852-01A1).

Precision targeting in the globus pallidus interna: insights from the multicenter, prospective, blinded VA/NINDS CSP 468 study.

Deep brain stimulation (DBS) targeting the globus pallidus interna (GPi) has been shown to significantly improve motor symptoms for the treatment of medication-refractory Parkinson's disease. Yet, heterogeneity in clinical outcomes persists, possibly due to suboptimal target identification within the GPi. By leveraging robust sampling of the GPi and 6-month postsurgical outcomes, this study aims to determine optimal symptom-specific GPi DBS targets. In this study, the authors analyzed the anatomical lead location and 6-month postsurgical, double-blinded outcome measures of 86 patients who underwent bilateral GPi DBS. These patients were selected from the multicenter Veterans Affairs (VA)/National Institutes of Neurological Disorders and Stroke (NINDS) Cooperative Studies Program (CSP) 468 study to identify the optimal target zones ("sweet spots") for the control of overall motor (United Parkinson's Disease Rating Scale [UPDRS]-III), axial, tremor, rigidity, and bradykinesia symptoms. Lead coordinates were normalized to Montreal Neurological Institute space and the optimal target zones were identified and validated using a leave-one-patient-out approach. The authors' findings revealed statistically significant optimal target zones for UPDRS-III (R = 0.37, p < 0.001), axial (R = 0.22, p = 0.042), rigidity (R = 0.20, p = 0.021), and bradykinesia (R = 0.23, p = 0.004) symptoms. These zones were localized within the primary motor and premotor subdivisions of the GPi. Interestingly, these zones extended beyond the GPi lateral border into the GPi-globus pallidus externa (GPe) lamina and into the GPe, but they did not reach the GPi ventral border, challenging traditional surgical approaches based on pallidotomies. Drawing upon a robust dataset, this research effectively delineates specific optimal target zones for not only overall motor improvement but also symptom subscores. These insights hold the potential to enhance the precision of targeting in subsequent bilateral GPi DBS surgical procedures.

The strength of the patellar and Achilles tendon reflexes is not affected in uncomplicated pregnancy.

Research on healthy pregnant women's reflexes is almost unheard of, even if an estimation of reflexes is a conventional part of the physical examination of preeclamptic patients, and hyperreflexia is generally considered to be a warning sign of eclampsia. The aim of the present study was to investigate the possible impact of gestation on tendon reflexes and the Babinski response, as examined in a clinical bed-side manner. A prospective, single-blind, cross-sectional study. Three study groups comprised non-pregnant (n = 20), 14-18 weeks (n = 16), and 34-38 weeks (n = 15) healthy pregnant women respectively. Two experienced neurologists examined separately each participant's patellar reflexes, Achilles reflexes, and Babinski response and rated them on two different scales, National Institute of Neurological Disorders and Stroke (NINDS) scale and Mayo Clinic Scale for Tendon Reflex Assessment. Inter-observer estimations between the patient groups and the neurologists were made by mixed effect model methodology. The patellar and Achilles reflexes´ strengths were rated similarly in all three groups (p > 0.05). The inter-observer difference was non-significant between the neurologists´ estimations (p > 0.05). The neurologists estimated the Babinski response in a few cases as neutral (0), otherwise down (normal). The patellar and Achilles reflex strengths are not affected in uncomplicated pregnancy. There is good concordance between neurologists´ estimations of tendon reflex strengths rated on the NINDS and Mayo scales.

Crizanlizumab for retinal vasculopathy with cerebral leukoencephalopathy in a phase II clinical study.

BackgroundRetinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a rare, autosomal dominant, universally fatal disease without effective treatment options. This study explores the safety and preliminary efficacy of crizanlizumab, a humanized monoclonal antibody against P-selectin approved for the prevention of sickle cell crises, in slowing retinal nonperfusion and preserving vision in patients with RVCL-S.METHODSEleven patients with RVCL-S with confirmed exonuclease 3 prime repair exonuclease 1 (TREX1) mutations received monthly crizanlizumab infusions over 2 years. The study measured the nonperfusion index within 3 retinal zones and the total retina with fluorescein angiography, visual acuity, intraocular pressure (IOP), and optical coherence tomography central subfield thickness (CST) at baseline, 1 year, and 2 years. A mixed repeated-measures analysis was performed to assess the progression rates and changes from baseline.RESULTSEleven participants received crizanlizumab infusions. All of the participants tolerated crizanlizumab well, with 8 of 11 (72.7%) reporting mild adverse effects such as nausea, fatigue, and gastrointestinal symptoms. The change in total retinal nonperfusion was 7.22% [4.47, 9.97] in year 1 and -0.69% [-4.06, 2.68] in year 2 (P < 0.001). In the mid periphery, the change in nonperfusion was 10.6% [5.1, 16.1] in year 1 and -0.68% [-3.98, 5.35] in year 2 (P < 0.01), demonstrating a reduction in progression of nonperfusion in the second year of treatment. Visual acuity, IOP, and CST remained stable.CONCLUSIONCrizanlizumab has an acceptable safety profile. These results show promising potential for examining crizanlizumab in larger studies of RVCL-S and similar small-vessel diseases and for using the retina as a biomarker for systemic disease.Trial registrationClinicalTrials.gov NCT04611880.FUNDINGThe Clayco Foundation; DeNardo Education and Research Foundation Grant; Jeffrey T. Fort Innovation Fund; Siteman Retina Research Fund; unrestricted grant from Research to Prevent Blindness Inc.; National Heart,Lung, and Blood Institute (NHLBI), NIH (R01HL129241); National Institute of Neurological Disorders and Stroke (NINDS), NIH (RF1NS116565).

Enhanced Human Skeletal Muscle Cell Differentiation via the Inhibition of 15-Hydroxyprostaglandin Dehydrogenase

Musculoskeletal diseases, including sarcopenia, are increasingly affecting billions globally. Individuals afflicted with such diseases experience impaired ability to regenerate muscle following injury or volumetric loss. Regeneration is vital for maintaining healthy muscle function and muscle cell differentiation plays a significant role. Our previous studies show that Prostaglandin E2 (PGE2) increases mouse muscle cell differentiation and improves muscle function. Adequate levels of PGE2 in muscle are therefore required for proper regeneration. 15-Hydroxyprostaglandin dehydrogenase (15-PDGH) is an enzyme which degrades PGE2. Previously, studies in rat muscle cells that were treated with SW0033291 (referred hereafter as SW), an inhibitor of 15-PDGH, showed that muscle cell differentiation was enhanced. There is no published study of SW effects on human skeletal muscle myogenesis. Our hypothesis is that when human skeletal muscle cells are treated with SW, the differentiation will be enhanced. To study the effects of SW on human muscle cell differentiation, first the cytotoxicity of SW on human primary skeletal muscle cells (HPSMC) from a young healthy woman were treated with 25, 50, 100, 500 and 1000nM SW for 24h and 48h. No cytotoxicity of SW was detected in all SW-treated groups compared to control group (p&gt;0.05). The effects of SW on myogenic differentiation were measured on day 4 using the methodology of Fusion Index (FI). To study the molecular mechanisms of SW on myogenesis, the expression of myogenic regulator genes (MyoD, MyoG and Mhc) were analyzed by RT-qPCR after the treatment of SW. At day 4 of differentiation, compared to control, no obvious difference of FI was found in 25, 50, 100, and 500nM SW-treated groups (p &gt; 0.05), while a significant increase in FI was found in the 1000nM (p &lt; 0.05) SW0033291-treated group (p&lt;0.05). These results suggest that SW enhances HPMC differentiation. Compared to control, in 25, 50, 100, and 500nM SW-treated groups, the expression of all three genes was not significantly changed (p &gt; 0.05). In the 1000nM SW-treated group, the expression of the myogenic markers MyoD, MyoG and Mhc increased significantly (p &lt; 0.05) by 1.83±0.21-fold, 1.47±0.18-fold, and 2.09±0.37-fold, respectively. These findings confirm our original hypothesis that SW enhances HPSMC differentiation. In conclusion, these results show initial promising application for maintaining proper PGE2 levels and thus allowing for proper human muscle cell differentiation and potential clinical applications in a wide range of musculoskeletal disorders. This work was directly supported by NIH-National Institutes of Aging P01AG039355 (MB) and the George W. and Hazel M. Jay and Evanston Research Endowments (MB). Authors were supported by NIH Grants: National Institutes of Aging (NINDS) 2-R01NS105621; NIA-R01AG056504, NIA-2R01AG060341, National Institutes of Diabetes, Digestive, and Kidney Diseases Kidney (NIDDK)-1R01DK119066 to MB, and National Institutes of Neurological Disorders and Stroke (NINDS) 2-R01NS105621 to MB. Also, NIH/NIDC 1R01DE031872-01 (VV). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Lipid Mapping of Lipid Signaling Mediators in Skeletal Muscle

Recent advancements in lipidomic have provided profound insight that goes beyond considering lipids as simple organic compounds that constitute the fundamental components of cell membranes. Beyond their pivotal roles in processes such as energy storage and serving as the fundamental building blocks of life, lipids have emerged as potent signaling molecules of significance. The importance of lipid signaling stems from its ability to orchestrate cellular responses to many environmental stresses, including salinity and pathogen attacks. Lipid signaling plays a significant role by allowing cells to respond to their local environment through reactions such as cell differentiation, inflammation and even immunity. In context with this knowledge, our objective is to comprehensively identify key signaling lipid mediators documented from published scientific literature, followed by a systemic visualization of the resulting data through the process of lipid mediator mapping to identify common signaling mediators pathways/networks that are essential for musculoskeletal (MSK) health and disease. These bioinformatics studies are complemented by our experimental studies in muscle cells. To this end, we are using a customized liquid chromatography-mass spectrometry (LC-MS) approach to profile and quantify lipid mediators (LMs). We were able to identify and profile up to 214 LMs and to precisely quantify 60 of them from various samples including body fluid, plasma, serum, bone marrow, muscle tissue, and other cell tissues. Preliminary screening indicated that 11,12-EET, 12-HETE, and PGE2 are three LMs that regulate physiologic aspects in muscles. In addition, 11,12-EET contributes to the regulation of vasodilation, exhibits anti-inflammatory properties under some conditions and in some specific tissues, and maintains endothelial function, and vascular health. However, our data indicates that 11, 12-EET levels increase with aging, decrease with exercise, and is causal for osteopenia in a zebrafish model, supporting our hypothesis that the effects of LMs are tissue specific and related to environmental factors. PGE2, which also causes inflammation, seems to be a putative LM implicated in tissue regeneration in multiple organs. In skeletal muscles, we found that PGE2 enhances myogenic differentiation and proliferation of muscle cells up to nM concentration. PGE2 also possesses beneficial bronchoprotective and anti-inflammatory effects on the airways. In conclusion, this combination of bioinformatics and experimental studies to deepen the mapping of signaling pathways and networks of LMs is crucially needed to understand the full function of LMs in MSK health and disease. This work was directly supported by NIH-National Institutes of Aging P01AG039355 (MB) and the George W. and Hazel M. Jay and Evanston Research Endowments (MB). Authors were supported by NIH Grants: National Institutes of Aging (NINDS) 2-R01NS105621; NIA-R01AG056504, NIA-2R01AG060341, National Institutes of Diabetes, Digestive, and Kidney Diseases Kidney (NIDDK)-1R01DK119066 to MB, and National Institutes of Neurological Disorders and Stroke (NINDS) 2-R01NS105621 to MB. Also, NIH/NIDC 1R01DE031872-01 (VV). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Liposome Loaded Prostaglandin E2 (PGE2) for Muscle Regeneration

Prostaglandin E2 (PGE2) is an FDA approved lipid signaling molecule for range of disorders. Also, it has a significant therapeutic potential for tissue repair and regeneration. However, to date there are no applications of PGE2 specifically designed for the muscle repair and regeneration. Liposome systems offer several advantages for PGE2 delivery, improved drug stability, reduced side effects, and tissue-specific targeting. Our hypothesis is that encapsulating PGE2 in liposome system will significantly enhance its bioavailability and maintain an effective therapeutic level. The research was designed to optimize PGE2 concentration in muscle cells, study its effect on cells differentiation, use the optimized PGE2 concentration for liposome-loading and testing the delivery system in-vitro and in-vivo using muscle injury models. We further investigated the molecular mechanism and signaling pathways triggered by the intracellular elevation of PGE2 in muscle cells. Optimization results revealed that nM concentration of PGE2 was beneficial while μM concentrations were detrimental. All our studies reported here were conducted with 50nM PGE2. 50nM PGE2 significantly enhances proliferation and myogenic differentiation as indicated by increased fusion index ( p=0.02) compared to a control. Scanning Electron Microscopy (SEM) images confirmed the lipid bi-layer formation with core-shell structure of 3μm liposomes containing PGE2. In-vitro studies on the C2C12 muscles cells showed that PGE2-liposome system significantly increased the intracellular concentration of PGE2 compared to a PGE2-vehicle (DMSO) control ( p=0.019), confirming the effcacy of this delivery system. Additionally, 50nM PGE2 significantly regulated myogenic signaling pathways and genes associated with calcium homeostasis, mitochondrial biogenesis, cellular hypertrophy, and oxidative stress. These findings support the notion that PGE2 induces the acceleration of myogenic differentiation which is supported by our initial signaling pathway analysis. Our in-vitro muscle damage model indicated that 50nM PGE2 can significantly attenuate the muscle damage and regenerate myotubes within 48 hours compared to 4 days in normal control. In conclusion, the findings suggest that liposome-PGE2 delivery system can positively influence myogenic differentiation, muscle properties, and cellular signaling pathways, offering promise for improving the delivery of PGE2 to injured skeletal muscles to assist in their regeneration process. This work was directly supported by NIH-National Institutes of Aging P01AG039355 (MB) and the George W. and Hazel M. Jay and Evanston Research Endowments (MB). Authors were supported by NIH Grants: National Institutes of Aging (NINDS) 2-R01NS105621; NIA-R01AG056504, NIA-2R01AG060341, National Institutes of Diabetes, Digestive, and Kidney Diseases Kidney (NIDDK)-1R01DK119066 to MB, and National Institutes of Neurological Disorders and Stroke (NINDS) 2-R01NS105621 to MB. Also, NIH/NIDC 1R01DE031872-01 (VV). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The SNX17-Retriever endosomal recycling pathway is a key regulator of synaptic function and plasticity in hippocampal neurons

The insertion and removal of integral membrane proteins is a key mechanism for the regulation of synaptic function. Once surface proteins are internalized, they can either be routed to lysosomes for degradation or can be recycled back to the cell surface. Two recycling protein complexes - the SNX27-Retromer complex and the recently discovered SNX17-Retriever complex - are the main drivers in recycling internalized cargoes in non-neuronal cells. In neurons, the SNX27-Retromer pathway has been shown to regulate surface expression of AMPA-type glutamate receptors (AMPARs) during long-term potentiation (LTP), but almost nothing is known regarding the role of the SNX17-Retriever pathway at synapses. Here, using cultured hippocampal neurons, we demonstrate that the SNX17-Retriever pathway localizes to both synaptic and extra-synaptic sites and that RNAi-mediated disruption of this pathway leads to the functional and structural loss of excitatory synapses. Moreover, we find that synaptic stimulation leads to the recruitment of SNX17 to synaptic sites in a manner that depends on Ca2+ influx through NMDARs, activation of CaMKII, and Retriever complex binding. Knockdown of either SNX17 or the Retriever subunit DSCR3 prevents structural plasticity of dendritic spines during LTP. Finally, this loss of structural plasticity is associated with altered traffcking of the cell adhesion molecule β1 Integrin, which is a SNX17 cargo in non-neuronal cells and as we show, in neurons as well. Additionally, SNX17-Retriever is shown to not play a role in AMPAR recycling. Preliminary studies suggest that SNX27 and SNX17 sort distinct cargos in neurons, suggesting that these two recycling pathways each play important, but unique, roles at synaptic sites. National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH) under award numbers R01-NS129198 to L.S. Weisman and M.A. Sutton, R01-NS099340 and R01- NS064015 to L.S. Weisman, R01-NS097498 to M.A. Sutton, and R21-NS125449, and R01-NS116008 to S. Iwase, by the National Institute of Mental Health (NIMH) of the NIH under award number R21-MH127485 to S. Iwase. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Imaging Findings in Acute Traumatic Brain Injury: a National Institute of Neurological Disorders and Stroke Common Data Element-Based Pictorial Review and Analysis of Over 4000 Admission Brain Computed Tomography Scans from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) Study.

In 2010, the National Institute of Neurological Disorders and Stroke (NINDS) created a set of common data elements (CDEs) to help standardize the assessment and reporting of imaging findings in traumatic brain injury (TBI). However, as opposed to other standardized radiology reporting systems, a visual overview and data to support the proposed standardized lexicon are lacking. We used over 4000 admission computed tomography (CT) scans of patients with TBI from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study to develop an extensive pictorial overview of the NINDS TBI CDEs, with visual examples and background information on individual pathoanatomical lesion types, up to the level of supplemental and emerging information (e.g., location and estimated volumes). We documented the frequency of lesion occurrence, aiming to quantify the relative importance of different CDEs for characterizing TBI, and performed a critical appraisal of our experience with the intent to inform updating of the CDEs. In addition, we investigated the co-occurrence and clustering of lesion types and the distribution of six CT classification systems. The median age of the 4087 patients in our dataset was 50 years (interquartile range, 29-66; range, 0-96), including 238 patients under 18 years old (5.8%). Traumatic subarachnoid hemorrhage (45.3%), skull fractures (37.4%), contusions (31.3%), and acute subdural hematoma (28.9%) were the most frequently occurring CT findings in acute TBI. The ranking of these lesions was the same in patients with mild TBI (baseline Glasgow Coma Scale [GCS] score 13-15) compared with those with moderate-severe TBI (baseline GCS score 3-12), but the frequency of occurrence was up to three times higher in moderate-severe TBI. In most TBI patients with CT abnormalities, there was co-occurrence and clustering of different lesion types, with significant differences between mild and moderate-severe TBI patients. More specifically, lesion patterns were more complex in moderate-severe TBI patients, with more co-existing lesions and more frequent signs of mass effect. These patients also had higher and more heterogeneous CT score distributions, associated with worse predicted outcomes. The critical appraisal of the NINDS CDEs was highly positive, but revealed that full assessment can be time consuming, that some CDEs had very low frequencies, and identified a few redundancies and ambiguity in some definitions. Whilst primarily developed for research, implementation of CDE templates for use in clinical practice is advocated, but this will require development of an abbreviated version. In conclusion, with this study, we provide an educational resource for clinicians and researchers to help assess, characterize, and report the vast and complex spectrum of imaging findings in patients with TBI. Our data provides a comprehensive overview of the contemporary landscape of TBI imaging pathology in Europe, and the findings can serve as empirical evidence for updating the current NINDS radiologic CDEs to version 3.0.

Research Education Programs—Residents, Fellows in Neurological Disorders and Stroke (NINDS)

Research Education Programs—Residents, Fellows in Neurological Disorders and Stroke (NINDS)

Usage of mineralocorticoids and isotonic crystalloids in subarachnoid hemorrhage patients in the United States

BackgroundThe usage rates of mineralocorticoids (fludrocortisone) to treat hyponatremia and isotonic crystalloids (saline and balanced crystalloids) to maintain intravascular volume in patients with aneurysmal subarachnoid hemorrhage (aSAH) patients across the United States are unknown. MethodsWe surveyed National Institute of Neurologic Disorders and Stroke (NINDS) StrokeNet sites in 2023, which are mostly large, tertiary, academic centers, and analyzed subarachnoid hemorrhage encounters from 2010 to 2020 in the Premier Healthcare Database that is representative of all types of hospitals and captures about 20 % of all acute inpatient care in the United States. ResultsAlthough mineralocorticoids are used by 70 % of the NINDS StrokeNet sites, it is used in less than 20 % of the aSAH encounters in the Premier Database. Although saline is ubiquitously used, balanced crystalloids are increasingly used for fluid therapy in aSAH patients. Its use in the NINDS StrokeNet sites and the Premier Healthcare Database is 41 and 45 %, respectively. ConclusionsThe use of mineralocorticoids remains low, and balanced crystalloids are increasingly used as fluid therapy in aSAH patients. The effectiveness of mineralocorticoids and balanced crystalloids in improving outcomes for aSAH patients must be rigorously tested in randomized clinical trials.

A 10 Year Analysis of Gender Distribution in National Institutes of Health Funding for Non-Malignant Hematology

Introduction: Historically, there has been an underrepresentation of women in the field of hematology. Consequently, this makes them less likely to receive academic research grants. Here, we present a ten year retrospective analysis of the Research Project Grants (R01) awarded by the National Institutes of Health (NIH) through the fiscal years of 2012-2022. The grants were categorized by various NIH agencies. This temporal analysis examines gender disparities under the field of non-malignant hematology research. Methods:Data was extracted for the fiscal years 2012-2022 focusing exclusively on R01 grants awarded and categorized by the various NIH agencies. Data was leveraged using the NIH RePORTER tool, Tidyverse, and janitor packages in R. The dataset incorporated key grant parameters such as grant ID, agency code, activity code, abstract text, project title, fiscal year, activity status, award amount, organization, and principal investigator's(PI) name. In order to distinguish a PI's gender, PI's first names were processed using the gender package in R, which provided a gender-wise distribution of recipients. For statistical analyses, proportions of females with accepted R01 grants were compared between 2012 to 2022; this proportion analysis was also done among each NIH agency. Further, linear regression and associated statistical tests were used to identify whether there was significant change in grants received by either gender over this time period. Results: A total of 250,031 R01 grants were awarded by the NIH during the fiscal years of 2012 to 2022. Females (n=82,152: 32.9% (95% CI 0.41-0.43) received fewer grants than males (n=167,879: 67.1%, (95% CI 0.50-0.55). Across 2012 to 2022, there was no significant change in R01 grants awarded among men (16,221 to 15,601, p-value= 0.52). In contrast, there was a significant difference for females in the R01 grants awarded across 2012 to 2022 (6,865 to 9,339, p-value &amp;lt;0.001). In 2012, the National Institute of General Medical Sciences (NIGMS), National Institute of Neurological Disorders and Stroke (NINDS), and National Institute of Biomedical Imaging and Bioengineering (NIBIB) awarded less than 25% of the total grants to females. By 2022, of all the agencies, the NBIB remained the agency with the most extensive gender gap with females being awarded only 23% of grants. In contrast, the National Institute of Minority Health and Disparities (NIMHD) and the National Institute of Nursing Research (NINR) were the only agencies in 2012 to award more grants to females with approximately 52% and 74% of grants respectively. In 2022, the NINR and NIHMD continued to show more grants awarded to females versus males. In addition to those agencies, by 2022, the National Institute of Child Health and Human Development(NICHD) and National Center for Complementary and Integrative Health (NCCIH) joined the NINR and NIHMD in awarding more than 50% of grants awarded to females that year. Conclusion: This analysis highlights continued gender disparity as only 33% of total R01 NIH grants were awarded to females during the fiscal years 2012-2022 in non-malignant hematologic research. Although, it is noted that while some agencies have made strides towards gender parity, others continue to have a significant gap. While this remains a systemic and multifaceted issue, identifying these areas of gender disparity will enable targeted efforts to bridge this gap and advance gender equality.

FRI433 Hypogonadism In Males With Adrenoleukodystrophy

Abstract Disclosure: J. Ramirez Alcantara: None. N. Grant: None. T.L. Stanley: Research Investigator; Self; Pfizer, Inc. F. Eichler: Consulting Fee; Self; consultant to Alnylam, Autobahn, Ionis, Minoryx, Orchard, Origen, Poxel, Takeda Therapeutics,and Taysha Gene Therapies, is a consultant to Third Rock Ventures on rare neurological disorders. Grant Recipient; Self; GLIA-CTN from National Institute of Neurological Disorders and Stroke (NINDS). Owner/Co-Owner; Self; founder of SwanBio Therapeutics. Research Investigator; Self; primary investigator (PI) of ex vivo lentiviral gene therapy trial in cerebral adrenoleukodystrophy sponsored by bluebird bio, the site-PI of Minoryx trial of leriglitazone for adrenomyeloneuropathy. N.A. Tritos: None. X-linked adrenoleukodystrophy (ALD) is a rare peroxisomal disorder caused by mutations in the ABCD1 gene. Little is known about the prevalence and characteristics of hypogonadism in ALD.We conducted a retrospective chart review to investigate hypogonadism in adult males with ALD. The presence of hypogonadism was determined by a clinician’s diagnosis and/or a total testosterone (TT) level below 249 ng/dL. Prospectively, we distributed a survey and evaluated serum gonadotropins and TT levels. The survey included the quantitative Saint Louis University Androgen Deficiency in the Aging Male (qADAM) questionnaire, a standardized screening tool for hypogonadism (score range: 10-50, lower scores indicate more symptoms). The normal laboratory ranges were 249-836 ng/dL (TT), 1-12 IU/L (FSH), and 2-12 IU/L (LH).We included 56 patients in the study (median age 36.2 years, range 19.3-72.4 years). Forty-seven (84%) patients had signs of myelopathy and 46 (82%) had adrenal insufficiency. Puberty data were available for 11 (20%) patients; two had documentation of delayed puberty onset, one of whom required testosterone treatment at age 15 years to jumpstart puberty. Thirty-one (55%) patients had erectile dysfunction and 24 (43%) used phosphodiesterase-5 inhibitors. Three patients had low libido and two had anorgasmia. Fifteen (27%) patients, two of whom required fertility treatment, had children. Nine (16%) patients had hypogonadism (median [IQR] age of diagnosis 37.4 [35.7,39.0] years), six of whom were on testosterone replacement. The median [IQR] TT level was 200 [143,240] ng/dL at the time of hypogonadism diagnosis. In patients with normal TT, the median [IQR] TT level was 498 [445,615] ng/dL. Twenty-two patients had LH levels and 18 had FSH levels available from clinical testing. In patients with hypogonadism, the median [IQR] levels for LH and FSH were 8.2 [7.2,8.4] and 8.3 [7.4,8.3] IU/L respectively. In patients with normal TT, the levels were 7.6 [5.7,10.4] and 4.0 [3.0,5.3] IU/L. There were no differences in LH or FSH levels between patients with normal TT and hypogonadism. Eight patients completed the prospective survey (median age 38.1 years). The median age of reported puberty onset was 13 years (range 12-15). Four patients, one of whom required fertility treatment, had children. Two (25%) patients reported low libido and 3 (38%) reported ED. The mean qADAM score was 36.5 (SD 5). We obtained prospective laboratory evaluation in ten patients. Median [IQR] levels were 564 [504,663] ng/dL (TT), 6.9 [5.4,9.8] IU/L (FSH), and 11 [7.2,13.8] IU/L (LH). In contrast to the retrospective clinical cohort, no patients had laboratory evidence of hypogonadism. Our results suggest that males with ALD may be at higher risk of developing central hypogonadism. In addition, ED and low libido may be present in males with ALD without laboratory evidence of hypogonadism. Presentation: Friday, June 16, 2023

Myalgic Encephalomyelitis-Chronic Fatigue Syndrome Common Data Element item content analysis.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multisystem chronic disease estimated to affect 836,000-2.5 million individuals in the United States. Persons with ME/CFS have a substantial reduction in their ability to engage in pre-illness levels of activity. Multiple symptoms include profound fatigue, post-exertional malaise, unrefreshing sleep, cognitive impairment, orthostatic intolerance, pain, and other symptoms persisting for more than 6 months. Diagnosis is challenging due to fluctuating and complex symptoms. ME/CFS Common Data Elements (CDEs) were identified in the National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (NINDS) Common Data Element Repository. This study reviewed ME/CFS CDEs item content. Inclusion criteria for CDEs (measures recommended for ME/CFS) analysis: 1) assesses symptoms; 2) developed for adults; 3) appropriate for patient reported outcome measure (PROM); 4) does not use visual or pictographic responses. Team members independently reviewed CDEs item content using the World Health Organization International Classification of Functioning, Disability and Health (ICF) framework to link meaningful concepts. 119 ME/CFS CDEs (measures) were reviewed and 38 met inclusion criteria, yielding 944 items linked to 1503 ICF meaningful concepts. Most concepts linked to ICF Body Functions component (b-codes; n = 1107, 73.65%) as follows: Fatiguability (n = 220, 14.64%), Energy Level (n = 166, 11.04%), Sleep Functions (n = 137, 9.12%), Emotional Functions (n = 131, 8.72%) and Pain (n = 120, 7.98%). Activities and Participation concepts (d codes) accounted for a smaller percentage of codes (n = 385, 25.62%). Most d codes were linked to the Mobility category (n = 69, 4.59%) and few items linked to Environmental Factors (e codes; n = 11, 0.73%). Relatively few items assess the impact of ME/CFS symptoms on Activities and Participation. Findings support development of ME/CFS-specific PROMs, including items that assess activity limitations and participation restrictions. Development of psychometrically-sound, symptom-based item banks administered as computerized adaptive tests can provide robust assessments to assist primary care providers in the diagnosis and care of patients with ME/CFS.