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The mevalonate pathway produces essential lipid metabolites such as cholesterol. Although this pathway is negatively regulated by metabolic intermediates, little is known of the metabolites that positively regulate its activity. We found that the amino acid glutamine is required to activate the mevalonate pathway. Glutamine starvation inhibited cholesterol synthesis and blocked transcription of the mevalonate pathway-even in the presence of glutamine derivatives such as ammonia and α-ketoglutarate. We pinpointed this glutamine-dependent effect to a loss in the ER-to-Golgi trafficking of SCAP that licenses the activation of SREBP2, the major transcriptional regulator of cholesterol synthesis. Both enforced Golgi-to-ER retro-translocation and the expression of a nuclear SREBP2 rescued mevalonate pathway activity during glutamine starvation. In a cell model of impaired mitochondrial respiration in which glutamine uptake is enhanced, SREBP2 activation and cellular cholesterol were increased. Thus, the mevalonate pathway senses and is activated by glutamine at a previously uncharacterized step, and the modulation of glutamine synthesis may be a strategy to regulate cholesterol levels in pathophysiological conditions., (© 2024. The Author(s).)

Clinical management and therapeutics development for Alzheimer's disease (AD) have entered a new era, with recent approvals of monoclonal antibody therapies targeting the underlying pathophysiology of the disease and modifying its trajectory. Imaging and fluid biomarkers are becoming increasingly important in the clinical development of AD therapeutics. This review focuses on the evidence of fluid biomarkers from recent amyloid-β-targeting clinical trials, summarizing biomarker data across 12 trials. It further proposes a simple framework to put biomarker guidance in the context of amyloid-pathway-targeted disease modification, delineates factors that impact biomarker data in clinical trials, and highlights knowledge gaps and future directions. Increased knowledge and data on biomarkers in the context of disease progression and disease modification will help to better design future AD trials and guide the clinical management of patients on AD-modifying therapies, bringing us closer to the implementation of precision medicine in AD., Competing Interests: Declaration of interests J.D. is an inventor on patents or patent applications of Eli Lilly and Company relating to the assays, methods, reagents and/or compositions of matter for p-tau assays and Aβ-targeting therapeutics. J.D. has served as a consultant or on advisory boards for Prevail Therapeutics, Eisai, Abbvie, Genotix Biotechnologies Inc., Gates Ventures, Karuna Therapeutics, AlzPath Inc., and Cognito Therapeutics, Inc. and received research support from Lilly, ADx Neurosciences, Fujirebio, AlzPath Inc., Roche Diagnostics, and Eli Lilly and Company in the past 2 years. J.D. has received speaker fees from LabCorp and Eli Lilly and Company. J.D. is a founder and advisor for Monument Biosciences. J.D. has stock or stock options in Eli Lilly and Company, Genotix Biotechnologies, AlzPath Inc., and Monument Biosciences. H.H. is an employee of Eisai and serves as reviewing editor for the Journal Alzheimer’s & Dementia. H.H. is inventor of 11 patents and has received no royalties for “In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders,” patent no. 8916388; “In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases,” patent no. 8298784; “Neurodegenerative Markers for Psychiatric Conditions,” publication no. 20120196300; “In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders,” publication no. 20100062463; “In Vitro Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders,” publication no. 20100035286; “In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases,” publication no. 20090263822; “In Vitro Method for The Diagnosis of Neurodegenerative Diseases,” patent no. 7547553; “CSF Diagnostic in Vitro Method for Diagnosis of Dementias and Neuroinflammatory Diseases,” publication no. 20080206797; “In Vitro Method for The Diagnosis of Neurodegenerative Diseases,” publication no. 20080199966; “Neurodegenerative Markers for Psychiatric Conditions,” publication no. 20080131921; “Method for Diagnosis of Dementias and Neuroinflammatory Diseases Based on an Increased Level of Procalcitonin in Cerebrospinal Fluid,” US patent no. 10921330. O.H. has acquired research support (for the institution) from AVID Radiopharmaceuticals, Biogen, C2N Diagnostics, Eli Lilly, Eisai, Fujirebio, GE Healthcare, and Roche. In the past 2 years, he has received consultancy/speaker fees from AC Immune, Alzpath, BioArctic, Biogen, Bristol Meyer Squibb, Cerveau, Eisai, Eli Lilly, Fujirebio, Merck, Novartis, Novo Nordisk, Roche, Sanofi, and Siemens. S.H. is an owner and employee of Pentara Corporation, a company that consults with dozens of companies in the Alzheimer’s space, including Biogen. No consulting fees were paid for work on this publication. Y.H., M.C., and P.S. are employees of Eisai., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Loss of proper T-cell functioning is a feature of aging that increases the risk of developing chronic diseases. In aged individuals, highly differentiated T cells arise with a reduced expression of CD28 and CD27 and an increased expression of KLRG-1 or CD57. These cells are often referred to as immunosenescent T cells but may still be highly active and contribute to autoimmunity. Another population of T cells known as exhausted T cells arises after chronic antigen stimulation and loses its effector functions, leading to a failure to combat malignancies and viral infections. A process called cellular senescence also increases during aging, and targeting this process has proven to be fruitful against a range of age-related pathologies in animal models. Cellular senescence occurs in cells that are irreparably damaged, limiting their proliferation and typically leading to chronic secretion of pro-inflammatory factors. To develop therapies against pathologies caused by defective T-cell function, it is important to understand the differences and similarities between immunosenescence and cellular senescence. Here, we review the hallmarks of cellular senescence versus senescent and exhausted T cells and provide considerations for the development of specific therapies against age-related diseases., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Spinocerebellar ataxias (SCA) are rare inherited neurodegenerative disorders characterized by a progressive impairment of gait, balance, limb coordination, and speech. There is currently no composite scale that includes multiple aspects of the SCA experience to assess disease progression and treatment effects. Applying the method of partial least squares (PLS) regression, we developed the Spinocerebellar Ataxia Composite Scale (SCACOMS) from two SCA natural history datasets (NCT01060371, NCT02440763). PLS regression selected items based on their ability to detect clinical decline, with optimized weights based on the item's degree of progression. Following model validation, SCACOMS was leveraged to examine disease progression and treatment effects in a 48-week SCA clinical trial cohort (NCT03701399). Items from the Clinical Global Impression-Global Improvement Scale (CGI-I), the Friedreich Ataxia Rating Scale (FARS) - functional stage, and the Modified Functional Scale for the Assessment and Rating of Ataxia (f-SARA) were objectively selected with weightings based on their sensitivity to clinical decline. The resulting SCACOMS exhibited improved sensitivity to disease progression and greater treatment effects (compared to the original scales from which they were derived) in a 48-week clinical trial of a novel therapeutic agent. The trial analyses also provided a SCACOMS-derived estimate of the temporal delay in SCA disease progression. SCACOMS is a useful composite measure, effectively capturing disease progression and highlighting treatment effects in patients with SCA. SCACOMS will be a powerful tool in future studies given its sensitivity to clinical decline and ability to detect a meaningful clinical impact of disease-modifying treatments., (© 2024. The Author(s).)

Introduction: Sodium phenylbutyrate and taurursodiol (PB and TURSO) is hypothesized to mitigate endoplasmic reticulum stress and mitochondrial dysfunction, two of many mechanisms implicated in Alzheimer's disease (AD) pathophysiology., Methods: The first-in-indication phase 2a PEGASUS trial was designed to gain insight into PB and TURSO effects on mechanistic targets of engagement and disease biology in AD. The primary clinical efficacy outcome was a global statistical test combining three endpoints relevant to disease trajectory (cognition [Mild/Moderate Alzheimer's Disease Composite Score], function [Functional Activities Questionnaire], and total hippocampal volume on magnetic resonance imaging). Secondary clinical outcomes included various cognitive, functional, and neuropsychiatric assessments. Cerebrospinal fluid (CSF) biomarkers spanning multiple pathophysiological pathways in AD were evaluated in participants with both baseline and Week 24 samples (exploratory outcome)., Results: PEGASUS enrolled 95 participants (intent-to-treat [ITT] cohort); cognitive assessments indicated significantly greater baseline cognitive impairment in the PB and TURSO ( n  = 51) versus placebo ( n  = 44) group. Clinical efficacy outcomes did not significantly differ between treatment groups in the ITT cohort. CSF interleukin-15 increased from baseline to Week 24 within the placebo group ( n  = 34). In the PB and TURSO group ( n  = 33), reductions were observed in core AD biomarkers phosphorylated tau-181 (p-tau181) and total tau; synaptic and neuronal degeneration biomarkers neurogranin and fatty acid binding protein-3 (FABP3); and gliosis biomarker chitinase 3-like protein 1 (YKL-40), while the oxidative stress marker 8-hydroxy-2-deoxyguanosine (8-OHdG) increased. Between-group differences were observed for the Aβ42/40 ratio, p-tau181, total tau, neurogranin, FABP3, YKL-40, interleukin-15, and 8-OHdG. Additional neurodegeneration, inflammation, and metabolic biomarkers showed no differences between groups., Discussion: While between-group differences in clinical outcomes were not observed, most likely due to the small sample size and relatively short treatment duration, exploratory biomarker analyses suggested that PB and TURSO engages multiple pathophysiologic pathways in AD., Highlights: Proteostasis and mitochondrial stress play key roles in Alzheimer's disease (AD).Sodium phenylbutyrate and taurursodiol (PB and TURSO) targets these mechanisms.The PEGASUS trial was designed to assess PB and TURSO effects on biologic AD targets.PB and TURSO reduced exploratory biomarkers of AD and neurodegeneration.Supports further clinical development of PB and TURSO in neurodegenerative diseases., Competing Interests: S.E.A. was the principal investigator of the PEGASUS trial and contributed to its design, conduct, statistical analyses of the exploratory biomarker assessments, writing and revision of this manuscript. S.E.A. reported receiving institutional grant or sponsored research support from the Alzheimer's Association, Alzheimer Drug Discovery Foundation, Challenger Foundation, John Sperling Foundation, National Institutes of Health, Prion Alliance, AbbVie Inc, AC Immune SA, Amylyx, Athira Pharma Inc, ChromaDex Inc, Cyclerion Therapeutics Inc, EIP Pharma Inc, Janssen Pharmaceutical/Johnson & Johnson, Ionis Pharmaceuticals, Novartis AG, Seer Bioscience Inc, vTv Therapeutics; honoraria for lectures from AbbVie Inc, Biogen Inc, and Eisai Co Ltd; payments for participation on scientific advisory boards of Allyx Therapeutics Inc, Bob's Last Marathon, Quince Therapeutics/Cortexyme Inc, Jocasta Neuroscience, and Sage Therapeutics Inc; consulting fees from Cognito Therapeutics Inc, Cassava Sciences, EIP Pharma Inc, M3 Biotechnology Inc, Orthogonal Neuroscience Inc, Risen Pharmaceutical Technology. S.H. is an employee and owner of Pentara Corporation, which was contracted to perform statistical analyses for the PEGASUS trial, including the clinical efficacy outcomes analyses described in this manuscript; reports consulting fees paid to Pentara from multiple pharmaceutical companies developing therapies for neurodegenerative diseases; and reports data safety monitoring board or advisory board fees from Alzheon, Eisai, and Prothena Biosciences paid to Pentara. J.N.‐J. and N.K. are employees of Pentara Corporation. V.J.W. reports consulting fees from Cognito Therapeutics, unrelated to the present manuscript, and an unpaid scientific advisory committee position in Division 40 of the American Psychological Association. J.M.B. reports clinical trial support from the National Institutes of Health, Eli Lilly, Biogen, AbbVie, AstraZeneca, and Roche, unrelated to the manuscript, and consulting fees from Amylyx Pharmaceuticals, Renew Research, Eisai, Eli Lilly, and Labcorp. M.C. reports grants from the American College of Radiology, the Alzheimer's Association, Novo Nordisk, Avanir Pharmaceuticals, Biogen, and the National Institutes of Health, all paid to the Tennessee Memory Disorders Foundation, and is an Alzheimer's Tennessee Board of Directors and Tennessee Memory Disorders Foundation volunteer. A.J.M. reports advisory board fees from Amylyx Pharmaceuticals and honoraria from the Alzheimer's Association Speaker's Bureau. S.N.V. reports grants to his affiliated institution from Biogen, Eisai, and Eli Lilly and participation on a data safety monitoring board or advisory board for Eli Lilly and Alector Therapeutics. Z.A. receives research support from the National Institutes of Health, Amylyx Pharmaceuticals, and Eli Lilly to her affiliated academic institution; lecture honoraria from Spire Learning and Summus; payment for expert testimony from the city of Naperville (government); support for attending professional society meetings from National Institutes of Health funds and academic institutions of higher learning; advisory board fees and consulting for non‐for‐profit (California Institute for Regenerative Medicine; international governmental funding agencies) and for‐profit organizations (including Eisai, Inc; Summus); and is a Specialty Chief Editor for Frontiers in Neurology. J.N. was the principal investigator for the Icahn School of Medicine at Mount Sinai (MSSM) PEGASUS trial site but was not compensated in this role; is a co‐director of the MSSM Alzheimer's Disease Research Center Outreach, Recruitment, and Engagement and Clinical Cores; and is editor of Focus on Healthy Aging. K.B. reports clinical trial support from Eisai and the Alzheimer's Clinical Trials Consortium, unrelated to this work, and fees for data monitoring committee participation from Eli Lilly. B.C.C. reports grants from the National Institutes of Health, Challenger Foundation, Bright Focus Foundation, Alzheimer's Research UK, and Ono Pharmaceutical to her affiliated institution; reports conference attendance support from Alzheimer's Research UK; and is an Academic Coordinator for the Alzheimer's Research UK Thames Valley Network. H.H.D. contributed to the statistical analyses in Table S4 of the exploratory biomarker assessments described in this manuscript and reports consulting fees from ALZpath and Biogen. R.E.T. is a paid consultant and shareholder in Amylyx Pharmaceuticals and was involved with the PEGASUS trial design and analyzing de‐identified trial results following the completion of the trial but not with the execution of the trial. P.D.Y. is the Chief Medical Officer and has stock and stock option ownership in Amylyx Pharmaceuticals. K.L. was an employee of Amylyx Pharmaceuticals from July 2015 through August 2021 and received stock options while employed with Amylyx Pharmaceuticals. B.A.T. and P.K. have no disclosures to report. Author disclosures are available in the Supporting Information., (© 2024 Amylyx Pharmaceuticals. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: This study explores the associations between pediatric adverse events (PAEs) and both hospital and patient characteristics within the inpatient hospital setting, specifically focusing on Neonatal Blood Stream Infection (NBSI) as defined by pediatric quality indicators (PDIs) from the Agency for Healthcare Research and Quality (AHRQ). This research aims to answer questions regarding the relationship between hospital characteristics and patient demographics with the occurrence of NBSI., Methods: This study utilized discharge data from the Healthcare Cost and Utilization Project (HCUP) Kids' Inpatient Databases (KID) for the year 2019. Bivariate and multivariate logistic regression models were employed to analyze patient-level encounters of NBSIs. The analysis examined various factors including hospital size, location, and teaching status, as well as patient-specific variables such as gender, age, race, service lines, payment sources, and major operating room procedures., Results: The results indicate that Public and Private not-for-profit hospitals showed significantly lower odds of experiencing NBSIs when compared to Private investor-owned hospitals, as did smaller, rural, and nonteaching hospitals when compared to large hospitals. Additionally, individual factors such as gender, age, race, service lines, payment sources, and types of major operating room procedures were found to have varying levels of significance in relation to NBSI., Conclusions: This study provides important insights into PAEs within the inpatient hospital setting, particularly focusing on NBSIs within the PDI framework. The findings highlight critical areas for the development of evidence-based interventions and guidelines, which are essential for clinicians and policymakers. Ultimately, this study contributes to the understanding and improvement of pediatric patient safety by emphasizing the necessity for targeted strategies to mitigate the risk of NBSI.

Site-one protease (S1P) conducts the first of two cleavage events in the Golgi to activate Sterol regulatory element binding proteins (SREBPs) and upregulate lipogenic transcription. S1P is also required for a wide array of additional signaling pathways. A zymogen serine protease, S1P matures through autoproteolysis of two pro-domains, with one cleavage event in the endoplasmic reticulum (ER) and the other in the Golgi. We recently identified the SREBP regulating gene, (SPRING), which enhances S1P maturation and is necessary for SREBP signaling. Here, we report the cryo-EM structures of S1P and S1P-SPRING at sub-2.5 Å resolution. SPRING activates S1P by dislodging its inhibitory pro-domain and stabilizing intra-domain contacts. Functionally, SPRING licenses S1P to cleave its cognate substrate, SREBP2. Our findings reveal an activation mechanism for S1P and provide insights into how spatial control of S1P activity underpins cholesterol homeostasis., (© 2024. The Author(s).)

Spinal cord injury (SCI) is a life-changing event that severely impacts the patient's quality of life. Modulating neuroinflammation, which exacerbates the primary injury, and stimulating neuro-regenerative repair mechanisms are key strategies to improve functional recovery. Cyclic adenosine monophosphate (cAMP) is a second messenger crucially involved in both processes. Following SCI, intracellular levels of cAMP are known to decrease over time. Therefore, preventing cAMP degradation represents a promising strategy to suppress inflammation while stimulating regeneration. Intracellular cAMP levels are controlled by its hydrolyzing enzymes phosphodiesterases (PDEs). The PDE4 family is most abundantly expressed in the central nervous system (CNS) and its inhibition has been shown to be therapeutically relevant for managing SCI pathology. Unfortunately, the use of full PDE4 inhibitors at therapeutic doses is associated with severe emetic side effects, hampering their translation toward clinical applications. Therefore, in this study, we evaluated the effect of inhibiting specific PDE4 subtypes (PDE4B and PDE4D) on inflammatory and regenerative processes following SCI, as inhibitors selective for these subtypes have been demonstrated to be well-tolerated. We reveal that administration of the PDE4D inhibitor Gebr32a, even when starting 2 dpi, but not the PDE4B inhibitor A33, improved functional as well as histopathological outcomes after SCI, comparable to results obtained with the full PDE4 inhibitor roflumilast. Furthermore, using a luminescent human iPSC-derived neurospheroid model, we show that PDE4D inhibition stabilizes neural viability by preventing apoptosis and stimulating neuronal differentiation. These findings strongly suggest that specific PDE4D inhibition offers a novel therapeutic approach for SCI., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MS, JP, and TV have a proprietary interest in selective PDE4D inhibitors for the treatment of demyelinating disorders and neurodegenerative disorders. RR, EF, OB, CB, and JP have a proprietary interest in the use of Gebr32a. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Alzheimer's Disease (AD) is a multifactorial, progressive neurodegenerative disease that disrupts synaptic and neuronal activity and network oscillations. It is characterized by neuronal loss, brain atrophy and a decline in cognitive and functional abilities. Cognito's Evoked Gamma Therapy System provides an innovative approach for AD by inducing EEG-verified gamma oscillations through sensory stimulation. Prior research has shown promising disease-modifying effects in experimental AD models. The present study (NCT03556280: OVERTURE) evaluated the feasibly, safety and efficacy of evoked gamma oscillation treatment using Cognito's medical device (CogTx-001) in participants with mild to moderate AD., Methods: The present study was a randomized, double blind, sham-controlled, 6-months clinical trial in participants with mild to moderate AD. The trial enrolled 76 participants, aged 50 or older, who met the clinical criteria for AD with baseline MMSE scores between 14 and 26. Participants were randomly assigned 2:1 to receive self-administered daily, one-hour, therapy, evoking EEG-verified gamma oscillations or sham treatment. The CogTx-001 device was use at home with the help of a care partner, over 6 months. The primary outcome measures were safety, evaluated by physical and neurological exams and monthly assessments of adverse events (AEs) and MRI, and tolerability, measured by device use. Although the trial was not statistically powered to evaluate potential efficacy outcomes, primary and secondary clinical outcome measures included several cognitive and functional endpoints., Results: Total AEs were similar between groups, there were no unexpected serious treatment related AEs, and no serious treatment-emergent AEs that led to study discontinuation. MRI did not show Amyloid-Related Imaging Abnormalities (ARIA) in any study participant. High adherence rates (85-90%) were observed in sham and treatment participants. There was no statistical separation between active and sham arm participants in primary outcome measure of MADCOMS or secondary outcome measure of CDR-SB or ADAS-Cog14. However, some secondary outcome measures including ADCS-ADL, MMSE, and MRI whole brain volume demonstrated reduced progression in active compared to sham treated participants, that achieved nominal significance., Conclusion: Our results demonstrate that 1-h daily treatment with Cognito's Evoked Gamma Therapy System (CogTx-001) was safe and well-tolerated and demonstrated potential clinical benefits in mild to moderate AD. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03556280., Competing Interests: MH, AB, EH, MS, AK, CS, VF, KK, BV, ZM, JM, and RK are employees and own stock options in Cognito Therapeutics, Inc. MH, CS, KK, BV, RK, JM, and ZM have patent applications assigned to Cognito Therapeutics, Inc. JN-J and SH are employees of Pentara who are contracted by Cognito Therapeutics for their service., (Copyright © 2024 Hajós, Boasso, Hempel, Shpokayte, Konisky, Seshagiri, Fomenko, Kwan, Nicodemus-Johnson, Hendrix, Vaughan, Kern, Megerian and Malchano.)

SREBP transcription factors are central regulators of lipid metabolism. Their proteolytic activation requires ER to the Golgi translocation and subsequent cleavage by site-1-protease (S1P). Produced as a proprotein, S1P undergoes autocatalytic cleavage from its precursor S1P A to mature S1P C form. Here, we report that SPRING (previously C12ORF29) and S1P interact through their ectodomains, and that this facilitates the autocatalytic cleavage of S1P A into its mature S1P C form. Reciprocally, we identified a S1P recognition-motif in SPRING and demonstrate that S1P-mediated cleavage leads to secretion of the SPRING ectodomain in cells, and in liver-specific Spring knockout (LKO) mice transduced with AAV-mSpring. By reconstituting SPRING variants into SPRING KO cells we show that the SPRING ectodomain supports proteolytic maturation of S1P and SREBP signaling, but that S1P-mediated SPRING cleavage is not essential for these processes. Absence of SPRING modestly diminishes proteolytic maturation of S1P A→C and trafficking of S1P C to the Golgi. However, despite reaching the Golgi in SPRING KO cells, S1P C fails to rescue SREBP signaling. Remarkably, whereas SREBP signaling was severely attenuated in SPRING KO cells and LKO mice, that of ATF6, another S1P substrate, was unaffected in these models. Collectively, our study positions SPRING as a dedicated licensing factor for SREBP-specific activation by S1P.