Neurological Disorders And Stroke Research Articles

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.

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.

Comparison of Guillain-Barre Syndrome Cases during and Prior to the COVID-19 Pandemic: A Multicentric Study.

Guillain-Barre syndrome (GBS) is one of the most common neurological manifestations associated with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Although data for a strong causal association is lacking, anecdotal reports, case series and systematic reviews linking the two have emerged in the literature. This prompted us to compare the clinical features, electrophysiology, and outcomes of GBS cases presenting during the pandemic with cases reported during a similar time period prior to the pandemic. Prospective data of GBS cases diagnosed as per the National Institute of Neurological Disorders and Stroke (NINDS) criteria was collected for a 6-month period (July-December 2021) at three tertiary care teaching hospitals during the coronavirus pandemic and compared with retrospective records-based data of cases prior to the pandemic (January-July 2019). A total of 40 cases were included in the cases, out of which 17 were in the prepandemic and 23 in the postpandemic period. A total of three cases temporally related to coronavirus disease 2019 (COVID-19) infection and four cases following COVID-19 vaccination were seen in the pandemic cohort. The clinical features, electrophysiological features, and outcomes were comparable during both periods. A slightly higher rate of in-hospital complications and single mortality was reported in the postpandemic period. The number of GBS hospital admissions, clinical presentation, electrodiagnostic features, and short-term outcomes did not differ significantly between the prepandemic and postpandemic periods; a slightly higher incidence of in-hospital complications was observed during the pandemic period. How to cite this article: Panicker P, R D, V AG, et al. Comparison of Guillain-Barre Syndrome Cases during and Prior to the COVID-19 Pandemic: A Multicentric Study. J Assoc Physicians India 2023;71(9):69-71.

Cerebral palsy pain instruments: Recommended tools for clinical research studies by the National Institute of Neurological Disorders and Stroke Cerebral Palsy Common Data Elements project.

This study describes the process of updating the cerebral palsy (CP) common data elements (CDEs), specifically identifying tools that capture the impact of chronic pain on children's functioning. Through a partnership between the American Academy for Cerebral Palsy and Developmental Medicine and the National Institute of Neurological Disorders and Stroke (NINDS), the CP CDEs were developed as data standards for clinical research in neuroscience. Chronic pain was underrepresented in the NINDS CP CDEs version 1.0. A multi-step methodology was applied by an interdisciplinary professional team. Following an adapted CP chronic pain tools' rating system, and a review of psychometric properties, clinical utility, and compliance with inclusion/exclusion criteria, a set of recommended pain tools was posted online for external public comment in May 2022. Fifteen chronic pain tools met inclusion criteria, representing constructs across all components of the International Classification of Functioning, Disability and Health. This paper describes the first condition-specific pain CDEs for a pediatric population. The proposed set of chronic pain tools complement and enhance the applicability of the existing pediatric CP CDEs. The novel CP CDE pain tools harmonize the assessment of chronic pain, addressing not only intensity of chronic pain, but also the functional impact of experiencing it in everyday activities.

Analysis of NINDS Health Disparities and Health Equity Research Portfolio, 2016-2020: Results and a Process for Transparency, Accuracy, and Reliability.

As detailed throughout this special issue, the National Institute of Neurological Disorders and Stroke (NINDS) recently undertook a strategic planning effort to guide the Institute's efforts and priorities in health disparities and health equity (HD/HE) research. One input into this effort was to conduct a 5-year longitudinal, in-depth analysis of NINDS-supported HD/HE research newly funded between the years 2016 and 2020. The goals of this analysis were to describe NINDS's portfolio according to consistent, contemporary definitions and HD/HE disciplinary theory. This required the development of a novel, systematic, and validated analysis protocol. The portfolio analysis was designed to inform the recommendations of an expert working group convened by the NINDS and internal efforts to support high-priority research, training, and infrastructure efforts. NINDS staff developed and validated this HD/HE research portfolio analysis protocol. Ultimately, HD/HE projects were characterized by their disease focus, populations of study, the health equity determinant(s) addressed, and the type and phase of research being conducted. For all interventional research, there was further assessment of the type and setting of intervention delivery as well as utilization of evidence-based community engagement and intervention sustainability approaches. A total of 58 new HD/HE research projects were funded from 2016 to 2020. The results of the descriptive analysis described here help provide a holistic picture of NINDS's HD/HE research portfolio, revealing strengths and gaps in the portfolio as well as opportunities ripe for future investment. NINDS developed a standardized HD/HE research categorization methodology with imbedded quality control checks that is intended to be transparent, accurate, and reproducible. The results of this HD/HE research portfolio analysis will serve as a baseline from which to assess the success of NINDS's research investments going forward.

Diversity, Equity, Inclusion, and Health Inequities Training in Neurologic Disorders and Stroke: Analysis and Recommendations From the NINDS Advisory Council Working Group.

In 2020, the National Institute of Neurological Disorders and Stroke (NINDS) leadership asked its Advisory Council to review NINDS efforts in the domains of diversity, equity, inclusion, and health inequities. Part of these efforts involved a focus on health equity training and health equity research workforce diversification activities. The objective of this article was to summarize the findings and make recommendations regarding these training activities. A subgroup of the National Advisory Neurological Disorders and Stroke Council Working Group for Health Disparities and Inequities in Neurological Disorders was engaged to advise NINDS leadership in the domain of diversity in health equity training. Activities included video teleconference meetings, multiple consultations with experienced leaders in the field, independent writing assignments, and an open public discussion as part of the NINDS HEADWAY workshop held on September 22-24, 2021. The working group recommends support for 2 distinct types of training activities: one designed for scientists from historically under-represented backgrounds and the second designed for scientists of all backgrounds performing health inequities research. Support for grant writing workshops and establishment of multi-institutional mentorship networks are recommended as potentially especially high-yield activities. The working group recommends that all NINDS-supported investigators should have sufficient diversity, equity, and inclusion training to be prepared and qualified to mentor trainees from under-represented backgrounds and mentor trainees engaged in health disparities research; there should be no "diversity tax" placed on established investigators from under-represented backgrounds to shoulder all the mentorship responsibilities. Among other recommendations, training in health disparities research should include a focus on interventional studies to alleviate inequities as well as social science and qualitative methods. There is a great deal of work to do in the field of diversity, equity, inclusion, and health inequities training, but we are optimistic that the activities outlined here, if fully implemented, will set us on the right track.

Advancing Health Equity in Neurologic Disorders and Stroke: Stakeholder Insights Into Health Disparities, Research Gaps, and Potential Interventions.

The purpose of this study was to analyze the National Institute of Neurological Disorders and Stroke (NINDS) Request for Information (RFI) input from the public-including health care providers, researchers, patients, patient advocates, caregivers, advocacy organizations, professional societies, and private and academic stakeholders with an interest in health disparities (HDs) in neurologic disease. RFI questions were structured to solicit input on what stakeholders believe are neurologic disease HD research priorities, drivers of health inequity, and potential interventions. Furthermore, these stakeholder insights were examined within the context of contemporary scientific literature and research frameworks on health equity and health disparities. The NINDS published a RFI from March 31 to July 15, 2020. The RFI analysis presented here is part of a larger strategic planning process aimed to guide future NINDS efforts in neurologic disorder health equity (HE) research and training. The public commented on facilitators of HDs, populations that experience HDs (HDPs), potential interventions, and research opportunities related to HDs in neurologic disease and/or care in the United States across the lifespan. Responses were analyzed using qualitative methodology. Frequently suggested interventions were thematically clustered using the interpretive phenomenological analysis methodology and are presented in this article to provide a stakeholder-identified roadmap for advancing HE. Respondents identified socioecological factors as driving HDs in 89% of determinants reported. Stakeholder-reported HD determinants and subsequent interventions could be classified into the following conceptual categories: HDP neurospecialty care access, innovative HDP engagement and research inclusion strategies, and development of a well-trained clinician-scientist HD workforce. Clustering of the feedback from patient and patient-adjacent respondents (i.e., caretakers and patient advocates) highlighted the prevalence of patient-provider interpersonal factors and limited resources driving access-to-care barriers among their sentiments. Respondent sentiments suggest prioritization of social determinants of health (SDOH) research, shifting away from the common target of biological and behavioral themes addressed in the existing body of HE research provided by the stakeholder. Overall, respondents suggest focusing research prioritization on access to care, engagement across the HE research and care landscape, and HE workforce development.

NINDS Health Equity Strategic Planning Process Overview, High-Level Recommendations, and Guide.

Neurologic mortality is increasing in the United States and is occurring in an inequitable manner. There is a major need for innovative research strategies to eliminate these inequities. In 2020, the National Institute of Neurological Disorders and Stroke (NINDS) embarked on a health equity strategic planning process, which culminated in a 3-day public workshop and research recommendations provided by a working group of its National Advisory Neurological Disorders and Stroke Council (NANDSC WG) to the NINDS. This Neurology® supplement is dedicated to the NINDS health equity strategic planning process. As cochairs of the NANDS WG, we developed this summary to provide an overview of the process and a guide for navigating this special issue. Detailed recommendations from the NANDS WG are distributed throughout various articles in this supplement and supported with extensive commentary on the state of the science in health equity. Consolidated high-level recommendations from this process are presented at the end of this article.

The Communication of Scientific Information to Scientists, Clinicians, and the Public: Recommendations for Achieving Health Equity.

Optimizing health care decisions relies critically on the availability of health-related information appropriate to the specific needs and circumstances of the individual. Abundant research has demonstrated that information relevant to health care decision-making reflects disparities along multiple axes of sex, race, socioeconomic status, geography, sexual orientation, and other factors. Compounding the problem is that mechanisms of access to information themselves, increasingly recognized as part of the social determinants of health, can perpetuate and even exacerbate these disparities. Critical to achieving neurologic health equity is the application of evidence-based strategies to inform the effective and efficient communication of information that can influence patients' behaviors, enhance community trust in the scientific enterprise, and shape health systems and policies. In 2020, as part of a strategic planning initiative, the National Institute of Neurological Disorders and Stroke (NINDS) charged its Advisory Council to form a working group of experts to provide recommendations for reducing health disparities. Here, we report our subgroup's findings, which focused on the role of communication in addressing neurologic disparities and inequities to achieve health equity. We find a need for incentivizing and supporting the application of communication science across the spectrum of neurologic health research. We present recommendations for NINDS and individual investigators to support communication activities that advance neurologic health equity.

Investigating T cell populations for immune cell exhaustion in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a devastating disease that confines ~65 million people worldwide to a life of pain, severe exhaustion, cognitive deficits, flu-like symptoms, and postexertional malaise. We previously discovered decreased glycolysis, decreased mitochondrial membrane potential, and increased fatty acid oxidation in ME/CFS T cells. These features are commonly found in exhausted T cells, a reversible state seen in chronic viral infections that decreases cell proliferation, survival, and cytotoxicity. Our study evaluated whether exhausted T cell subsets circulate in people with ME/CFS by analyzing CD4+ and CD8+ T cells for associated inhibitory receptors and transcription factors. CD4+ and CD8+ T cells were isolated from 20 patients and 20 sedentary control blood samples and measured for ~15–17 markers at rest and after stimulation using a FACSymphony analyzer. Markers included cell population identifiers for naïve, effector, memory, regulatory, and helper T cells. We found significantly higher abundances and frequencies of transcription factors related to exhaustion in general and within PD-1+ CD8+ T cells in ME/CFS samples. Half of the ME/CFS cohort showed higher PD-1 memory CD8+ T cell frequencies than the control group. Moreover, ME/CFS CD4+ T cells exhibited higher levels of Lag3, CTLA4, and T-bet in various subsets. This research detects a novel state of immune cell dysfunction in ME/CFS that may suggest new treatment options. Supported by the Alfred P. Sloan Foundation and the National Institute of Neurological Disorders and Stroke (NINDS), NIH (U54NS105541).