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Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and indications for postoperative radiotherapy are controversial. Here we develop a targeted gene expression biomarker that predicts meningioma outcomes and radiotherapy responses. Using a discovery cohort of 173 meningiomas, we developed a 34-gene expression risk score and performed clinical and analytical validation of this biomarker on independent meningiomas from 12 institutions across 3 continents (N = 1,856), including 103 meningiomas from a prospective clinical trial. The gene expression biomarker improved discrimination of outcomes compared with all other systems tested (N = 9) in the clinical validation cohort for local recurrence (5-year area under the curve (AUC) 0.81) and overall survival (5-year AUC 0.80). The increase in AUC compared with the standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval 0.07 to 0.17, P

BackgroundMeningiomas are the most common primary intracranial tumor in adults. Clinical care is currently guided by the World Health Organization (WHO) grade assigned to meningiomas, a 3-tiered grading system based on histopathology features, as well as extent of surgical resection. Clinical behavior, however, often fails to conform to the WHO grade. Additional prognostic information is needed to optimize patient management.MethodsWe evaluated whether chromosomal copy-number data improved prediction of time-to-recurrence for patients with meningioma who were treated with surgery, relative to the WHO schema. The models were developed using Cox proportional hazards, random survival forest, and gradient boosting in a discovery cohort of 527 meningioma patients and validated in 2 independent cohorts of 172 meningioma patients characterized by orthogonal genomic platforms.ResultsWe developed a 3-tiered grading scheme (Integrated Grades 1-3), which incorporated mitotic count and loss of chromosome 1p, 3p, 4, 6, 10, 14q, 18, 19, or CDKN2A. 32% of meningiomas reclassified to either a lower-risk or higher-risk Integrated Grade compared to their assigned WHO grade. The Integrated Grade more accurately identified meningioma patients at risk for recurrence, relative to the WHO grade, as determined by time-dependent area under the curve, average precision, and the Brier score.ConclusionWe propose a molecularly integrated grading scheme for meningiomas that significantly improves upon the current WHO grading system in prediction of progression-free survival. This framework can be broadly adopted by clinicians with relative ease using widely available genomic technologies and presents an advance in the care of meningioma patients.

The Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) is a hybrid of the Mediterranean and DASH (Dietary Approaches to Stop Hypertension) diets, and its association with renal outcomes remains unclear. In the REasons for Geographic and Racial Disparities in Stroke (REGARDS) cohort, diet data were collected at baseline using food frequency questionnaires. Modified Poisson regression was used to examine the association of MIND diet with incident chronic kidney disease (CKD). In the REGARDS stroke case-cohort, 357 metabolites were measured in baseline plasma. Weighted linear regression was used to test associations between MIND diet and metabolites. Weighted logistic regression was used to test associations between MIND-associated metabolites and incident CKD. Mediation analyses were conducted to determine whether metabolites mediated the relationship between MIND diet and CKD. A higher MIND diet score was associated with a decreased risk of incident CKD (risk ratio 0.90, 95% CI (0.86–0.94); p = 2.03 × 10−7). Fifty-seven metabolites were associated with MIND diet (p < 3 × 10−4). Guanosine was found to mediate the relationship between MIND diet and incident CKD (odds ratio for indirect effects 0.93, 95% CI (0.88–0.97); p < 0.05). These findings suggest a role of the MIND diet in renal outcomes. [ABSTRACT FROM AUTHOR]

Objective: While dietary intake is linked to stroke risk, surrogate markers that could inform personalized dietary interventions are lacking. We identified metabolites associated with diet patterns and incident stroke in a nested cohort from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. Methods: Levels of 162 metabolites were measured in baseline plasma from stroke cases (n = 1,198) and random controls (n = 904). We examined associations between metabolites and a plant‐based diet pattern previously linked to reduced stroke risk in REGARDS. Secondary analyses included 3 additional stroke‐associated diet patterns: a Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and Southern diet. Metabolites were tested using Cox proportional hazards models with incident stroke as the outcome. Replication was performed in the Jackson Heart Study (JHS). Inverse odds ratio‐weighted mediation was used to determine whether metabolites mediated the association between a plant‐based diet and stroke risk. Results: Metabolites associated with a plant‐based diet included the gut metabolite indole‐3‐propionic acid (β = 0.23, 95% confidence interval [CI] [0.14, 0.33], p = 1.14 × 10−6), guanosine (β = −0.13, 95% CI [−0.19, −0.07], p = 6.48 × 10−5), gluconic acid (β = −0.11, 95% CI [−0.18, −0.04], p = 2.06 × 10−3), and C7 carnitine (β = −0.16, 95% CI [−0.24, −0.09], p = 4.14 × 10−5). All of these metabolites were associated with both additional diet patterns and altered stroke risk. Mediation analyses identified guanosine (32.6% mediation, p = 1.51 × 10−3), gluconic acid (35.7%, p = 2.28 × 10−3), and C7 carnitine (26.2%, p = 1.88 × 10−2) as mediators linking a plant‐based diet to reduced stroke risk. Interpretation: A subset of diet‐related metabolites are associated with risk of stroke. These metabolites could serve as surrogate markers that inform dietary interventions. ANN NEUROL 2023;93:500–510 [ABSTRACT FROM AUTHOR]

Cerebral revascularization surgery has been advanced by the refinement of several adjunctive tools. These tools include perioperative blood thinners, intraoperative spasmolytic agents, electrophysiological monitoring, and methods for assessing bypass patency or marking arteriotomies. Despite the array of options, the proper usage and comparative advantages of different complements in cerebral bypass have not been well-cataloged elsewhere. In this literature review, we describe the appropriate usage, benefits, and limitations of various bypass adjuncts. Understanding these adjuncts can help surgeons ensure that they receive reliable intraoperative information about bypass function and minimize the risk of serious complications. Overall, this review provides a succinct reference for neurosurgeons on various cerebrovascular bypass adjuncts. [ABSTRACT FROM AUTHOR]

The central nervous system (CNS) plays a key role in the sense-and-respond system which maintains proper energy stores. However, the molecular, cellular, and circuit mechanisms through which the CNS achieves this goal is poorly understood. We have recently identified the dorsal raphe nucleus (DRN) as a key node in the CNS, responsible for regulating numerous aspects of energy balance. Neurons within the DRN can potently regulate feeding, thermogenesis, and locomotor activity, and prolonged changes in their activity can ultimately drive changes in body weight. Despite playing a key role in regulating energy homeostasis, the molecular heterogeneity of the DRN had, until recently, hindered further progress in understanding it's intricate role in the regulation of body weight. Here, we use a combination of nuclear labeling, sorting, and single-nuclear RNA-sequencing to identify the component cell types of key DRN populations, themselves known to regulate the various facets of energy balance. In particular, we identify over twenty candidate subpopulations of DRN neurons, principally defined by the neurotransmitters serotonin, glutamate, and GABA. Many of the subpopulations of these 'principal' cell types differentially express peptides, receptors, and signaling molecules that are directly implicated in the regulation of energy balance. We have begun to validate the expression and neuroanatomy of these molecules, including such neuropeptides as thyrotropin-releasing hormone and neuropeptide Y, and we have leveraged available recombinase-driver lines to modulate the activity of neurons expressing these genes to effectively assay their function. Together, this work represents important progress towards identifying the key cell subtypes that regulate the various aspects of energy balance. Disclosure: V. M. Bhave: None. M. J. Hill-oliva: None. N. Kamatkar: None. S. Chowdhury: None. A. R. Nectow: None. Funding: American Diabetes Association/Pathway to Stop Diabetes (1-18-ACE-49 to A.R.N.) [ABSTRACT FROM AUTHOR]

An important goal in metabolism is to identify brain regions capable of regulating energy balance. These brain regions represent potential druggable targets for the modification of food intake and energy expenditure, which could help to combat any number of debilitating disorders relating to metabolic function and body weight. We have recently identified the dorsal raphe nucleus (DRN) as a key node in the central nervous system regulating both food intake and energy expenditure. In particular, we have found that inhibitory, GABAergic neurons residing in the dorsolateral aspect of this nucleus are activated by hunger and in turn induce the appropriate counterregulatory responses – namely, to increase food intake and suppress energy expenditure. Here, using a combination of ensemble-level molecular profiling in tandem with single-nuclear RNA sequencing, we demonstrate that these GABAergic neurons are molecularly heterogeneous and express a host of factors directly implicated in the central control of energy homeostasis. Of note, a few of these subpopulations express abundant levels of transcript for neuropeptides important in regulating energy balance, such as thyrotropin-releasing hormone (Trh) and neuropeptide Y (Npy). These profiling studies thus demonstrate a previously underappreciated level of heterogeneity within GABAergic neurons of the DRN suggesting a multifaceted, and possibly distributed, mechanism through which these neurons may regulate energy balance. Together, this work molecularly characterizes the DRN at a resolution not previously possible and identifies cell subpopulations through which this nucleus may regulate energy homeostasis. Disclosure: V.M. Bhave: None. N. Kamatkar: None. A.R. Nectow: None. Funding: American Diabetes Association/Pathway to Stop Diabetes (1-18-ACE-49 to A.R.N.); American Diabetes Association (1-18-IBS-148 to A.R.N.); Foundation for Prader-Willi Research; National Alliance for Research on Schizophrenia & Depression [ABSTRACT FROM AUTHOR]

Background: With the significant shift in the classification, risk stratification, and standards of care for gliomas, we sought to understand how the overall survival of patients with these tumors is impacted by molecular features, clinical metrics, and treatment received., Methods: We assembled a cohort of patients with a histopathologically diagnosed glioma from The Cancer Genome Atlas, Project Genomics Evidence Neoplasia Information Exchange, and Dana-Farber Cancer Institute/Brigham and Women's Hospital. This incorporated retrospective clinical, histological, and molecular data alongside prospective assessment of patient survival., Results: 4,400 gliomas were identified: 2,195 glioblastoma, 1,198 IDH1/2-mutant astrocytoma, 531 oligodendroglioma, 271 other IDH1/2-wildtype glioma, and 205 pediatric-type glioma. Molecular classification updated 27.2% of gliomas from their original histopathologic diagnosis. Examining the distribution of molecular alterations across glioma subtypes revealed mutually exclusive alterations within tumorigenic pathways. Non-TCGA patients had significantly improved overall survival compared to TCGA patients, with 26.7%, 55.6%, and 127.8% longer survival for glioblastoma, IDH1/2-mutant astrocytoma, and oligodendroglioma respectively (all p<0.01). Several prognostic features were characterized, including NF1 alteration and 21q loss in glioblastoma, and EGFR amplification and 22q loss in IDH1/2-mutant astrocytoma. Leveraging the size of this cohort, nomograms were generated to assess the probability of overall survival based on patient age, the molecular features of a tumor, and the treatment received., Conclusions: By applying modern molecular criteria, we characterize the genomic diversity across glioma subtypes, identify clinically applicable prognostic features, and provide a contemporary update on patient survival to serve as a reference for ongoing investigations., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Purpose: Adverse clinical events cause significant morbidity in patients with GBM (GBM). We examined whether genomic alterations were associated with AE (AE) in patients with GBM., Experimental Design: We identified adults with histologically confirmed IDH-wild-type GBM with targeted next-generation sequencing (OncoPanel) at Dana Farber Cancer Institute from 2013 to 2019. Seizure at presentation, lymphopenia, thromboembolic events, pseudoprogression, and early progression (within 6 months of diagnosis) were identified as AE. The biologic function of genetic variants was categorized as loss-of-function (LoF), no change in function, or gain-of-function (GoF) using a somatic tumor mutation knowledge base (OncoKB) and consensus protein function predictions. Associations between functional genomic alterations and AE were examined using univariate logistic regressions and multivariable regressions adjusted for additional clinical predictors., Results: Our study included 470 patients diagnosed with GBM who met the study criteria. We focused on 105 genes that had sequencing data available for ≥ 90% of the patients and were altered in ≥10% of the cohort. Following false-discovery rate (FDR) correction and multivariable adjustment, the TP53, RB1, IGF1R, and DIS3 LoF alterations were associated with lower odds of seizures, while EGFR, SMARCA4, GNA11, BRD4, and TCF3 GoF and SETD2 LoF alterations were associated with higher odds of seizures. For all other AE of interest, no significant associations were found with genomic alterations following FDR correction., Conclusions: Genomic biomarkers based on functional variant analysis of a routine clinical panel may help identify AE in GBM, particularly seizures. Identifying these risk factors could improve the management of patients through better supportive care and consideration of prophylactic therapies., (©2024 American Association for Cancer Research.)