Associations Between Ultra-Processed Food Consumption and Adverse Brain Health Outcomes.

BACKGROUND AND OBJECTIVES: Ultra-processed foods (UPFs) are linked to cardiometabolic diseases and neurologic outcomes, such as cognitive decline and stroke. However, it is unclear whether food processing confers neurologic risk independent of dietary pattern information. We aimed to (1) investigate associations between UPFs and incident cognitive impairment and stroke and (2) compare these associations with other commonly recommended dietary patterns in the REasons for Geographic and Racial Differences in Stroke study. This prospective, observational cohort study enrolled Black and White adults in the United States from 2003 to 2007. METHODS: The NOVA system was used to categorize items from a baseline food frequency questionnaire according to the level of processing. Participants with incomplete or implausible self-reported dietary data were excluded. Consumption for each category (grams) was normalized to total grams consumed. Scores quantifying adherence to a Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet were also calculated. Incident cognitive impairment was defined using performance relative to a normative sample on memory and fluency assessments. Incident stroke was identified through adjudicated review of medical records. RESULTS: The cognitive impairment cohort (n = 14,175) included participants without evidence of impairment at baseline who underwent follow-up testing. The stroke cohort (n = 20,243) included participants without a history of stroke. In multivariable Cox proportional hazards models, a 10% increase in relative intake of UPFs was associated with higher risk of cognitive impairment (hazard ratio [HR] = 1.16, 95% CI 1.09-1.24, p = 1.01 × 10-5) and intake of unprocessed or minimally processed foods with lower risk of cognitive impairment (HR = 0.88, 95% CI 0.83-0.94, p = 1.83 × 10-4). Greater intake of UPFs (HR = 1.08, 95% CI 1.02-1.14, p = 1.12 × 10-2) and unprocessed or minimally processed foods (HR = 0.91, 95% CI 0.86-0.95, p = 2.13 × 10-4) were also associated with risk of stroke in multivariable Cox models. The effect of UPFs on stroke risk was greater among Black than White participants (UPF-by-race interaction HR = 1.15, 95% CI 1.03-1.29, p = 1.50 × 10-2). Associations between UPFs and both cognitive impairment and stroke were independent of adherence to the Mediterranean, DASH, and MIND diets. DISCUSSION: Food processing may be important to brain health in older adults independent of known risk factors and adherence to recommended dietary patterns.

Workplace food purchases, dietary intake, and gut microbial metabolites in a secondary analysis of the ChooseWell 365 study.

BACKGROUND: Dietary choices can affect human health through alterations in gut microbial metabolism, and gut microbial metabolites could serve as biomarkers for disease risk conferred by dietary intake. However, self-reported dietary intake may not reflect true intake. OBJECTIVES: We identified circulating metabolites, including gut microbiome-related metabolites, associated with adherence to a healthy diet in the ChooseWell 365 study. In this randomized clinical trial, the dietary choices of hospital employees were assessed over 24 mo using not only 24-h dietary recalls but also electronic records of hospital cafeteria purchases. METHODS: Plasma metabolites were profiled from 470 participants. Two targeted metabolomics methods were developed and implemented to expand detection coverage for metabolites related to gut microbial activity. Linear regression models were used to associate metabolites with Healthy Purchasing Scores (HPSs) derived from cafeteria purchases and Healthy Eating Index-2015 (HEI-15) scores derived from dietary recalls. RESULTS: Fourteen metabolites were concordantly associated with the HPS and HEI-15 scores in multivariable models adjusted for age, gender, and race, including the gut microbiome-related metabolites indole-3-propionic acid (HPS, ß: 0.16, 95% CI: 0.07, 0.26, P = 7.32 × 10-4; HEI-15, ß: 0.16, 95% CI: 0.07, 0.25, P = 6.79 × 10-4), hippuric acid (HPS, ß: 0.11, 95% CI: 0.02, 0.21, P = 1.97 × 10-2; HEI-15, ß: 0.10, 95% CI: 0.01, 0.19, P = 3.14 × 10-2), and indoxyl sulfate (HPS, ß = -0.13, 95% CI: -0.23, -0.03, P = 8.21 × 10-3; HEI-15, ß: -0.12, 95% CI: -0.22, -0.03, P = 8.50 × 10-3). These gut microbial metabolites were associated with the intake of specific food groups, such as whole fruits. These metabolites were also associated with clinical variables, including blood pressure, diabetes or prediabetes, and body mass index. CONCLUSIONS: In a secondary analysis of the ChooseWell 365 study, associations between circulating gut microbiome-related metabolites and a healthy diet were confirmed using both objective and subjective measures of consumption. Accurate identification of diet-associated metabolites may help guide dietary or microbiome-based interventions aimed at disease prevention.

Omega-3 Fatty Acids and Risk of Ischemic Stroke in REGARDS.

We examined associations between lipidomic profiles and incident ischemic stroke in the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. Plasma lipids (n = 195) were measured from baseline blood samples, and lipids were consolidated into underlying factors using exploratory factor analysis. Cox proportional hazards models were used to test associations between lipid factors and incident stroke, linear regressions to determine associations between dietary intake and lipid factors, and the inverse odds ratio weighting (IORW) approach to test mediation. The study followed participants over a median (IQR) of 7 (3.4-11) years, and the case-cohort substudy included 1075 incident ischemic stroke and 968 non-stroke participants. One lipid factor, enriched for docosahexaenoic acid (DHA, an omega-3 fatty acid), was inversely associated with stroke risk in a base model (HR = 0.84; 95%CI 0.79-0.90; P = 8.33 × 10-8) and fully adjusted model (HR = 0.88; 95%CI 0.83-0.94; P = 2.79 × 10-4). This factor was associated with a healthy diet pattern (ß = 0.21; 95%CI 0.12-0.30; P = 2.06 × 10-6), specifically with fish intake (ß = 1.96; 95%CI 0.95-2.96; P = 1.36 × 10-4). DHA was a mediator between fish intake and incident ischemic stroke (30% P = 5.78 × 10-3). Taken together, DHA-containing plasma lipids were inversely associated with incident ischemic stroke and mediated the relationship between fish intake and stroke risk.

Sex-Associated Metabolites and Incident Stroke, Incident Coronary Heart Disease, Hypertension, and Chronic Kidney Disease in the REGARDS Cohort.

BACKGROUND: Sex disparities exist in cardiometabolic diseases. Metabolomic profiling offers insight into disease mechanisms, as the metabolome is influenced by environmental and genetic factors. We identified metabolites associated with sex and determined if sex-associated metabolites are associated with incident stoke, incident coronary heart disease, prevalent hypertension, and prevalent chronic kidney disease. METHODS AND RESULTS: Targeted metabolomics was conducted for 357 metabolites in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) case-cohort substudy for incident stroke. Weighted logistic regression models were used to identify metabolites associated with sex in REGARDS. Sex-associated metabolites were replicated in the HyperGEN (Hypertension Genetic Epidemiology Network) and using the literature. Weighted Cox proportional hazard models were used to evaluate associations between metabolites and incident stroke. Cox proportional hazard models were used to evaluate associations between metabolites and incident coronary heart disease. Weighted logistic regression models were used to evaluate associations between metabolites and hypertension and chronic kidney disease. Fifty-one replicated metabolites were associated with sex. Higher levels of 6 phosphatidylethanolamines were associated with incident stroke. No metabolites were associated with incident coronary heart disease. Higher levels of uric acid and leucine and lower levels of a lysophosphatidylcholine were associated with hypertension. Higher levels of indole-3-lactic acid, 7 phosphatidylethanolamines, and uric acid, and lower levels of betaine and bilirubin were associated with chronic kidney disease. CONCLUSIONS: These findings suggest that the sexual dimorphism of the metabolome may contribute to sex differences in stroke, hypertension, and chronic kidney disease.

Plasma Metabolites and Life's Simple 7 in REGARDS.

BACKGROUND: The American Heart Association's Life's Simple 7 (LS7) is a health metric that captures important factors associated with cardiovascular and cerebrovascular health. Previous studies highlight the potential of plasma metabolites to serve as a marker for lifestyle and health behavior that could be a target for stroke prevention. The objectives of this study were to identify metabolites that were associated with LS7 and incident ischemic stroke and mediate the relationship between the two. METHODS: Targeted metabolomic profiling of 162 metabolites by liquid chromatography-tandem mass spectrometry was used to identify candidate metabolites in a stroke case-cohort nested within the REGARDS study (Reasons for Geographic and Racial Differences in Stroke). Weighted linear regression and weighted Cox proportional hazard models were used to identify metabolites that were associated with LS7 and incident ischemic stroke, respectively. Effect measures were based on a 1-SD change in metabolite level. Metabolite mediators were examined using inverse odds ratio weighting mediation analysis. RESULTS: The study comprised 1075 ischemic stroke cases and 968 participants in the random cohort sample. Three out of 162 metabolites were associated with the overall LS7 score including guanosine (ß, -0.46 [95% CI, -0.65 to -0.27]; P=2.87×10-6), cotinine (ß, -0.49 [95% CI, -0.70 to -0.28]; P=7.74×10-6), and acetylneuraminic acid (ß, -0.59 [95% CI, -0.77 to -0.42]; P=4.29×10-11). Guanosine (hazard ratio, 1.47 [95% CI, 1.31-1.65]; P=6.97×10-11), cotinine (hazard ratio, 1.30 [95% CI, 1.16-1.44]; P=2.09×10-6), and acetylneuraminic acid (hazard ratio, 1.29 [95% CI, 1.15-1.45]; P=9.24×10-6) were associated with incident ischemic stroke. The mediation analysis identified guanosine (27% mediation, indirect effect; P=0.002), cotinine (30% mediation, indirect effect; P=0.004), and acetylneurminic acid (22% mediation, indirect effect; P=0.041) partially mediated the relationship between LS7 and ischemic stroke. CONCLUSIONS: We identified guanosine, cotinine, and acetylneuraminic acid that were associated with LS7, incident ischemic stroke, and mediated the relationship between LS7 and ischemic stroke.

Clinical and Genomic Predictors of Adverse Events in Newly Diagnosed Glioblastoma.

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.

Reduced Mortality and Radiation Necrosis After Surgery With Postoperative Stereotactic Radiation in Patients With Multiple Brain Metastases.

BACKGROUND AND OBJECTIVES: Although stereotactic radiation has frequently supplanted whole-brain radiation therapy (WBRT) in treating patients with multiple brain metastases, the role of surgery for these patients remains unresolved. No randomized trials have compared surgical resection with postoperative stereotactic radiosurgery (SRS) or stereotactic radiotherapy (SRT) to SRS/SRT alone. Previous studies addressing surgery for patients with multiple brain metastases are often limited by small sample sizes, a lack of appropriate comparison groups, or a focus on patients treated before recent advances in targeted therapy and immunotherapy. We compared outcomes in patients with multiple brain metastases treated with surgical resection and postoperative SRS/SRT to those treated with SRS/SRT alone. METHODS: We studied 734 patients with multiple newly diagnosed brain metastases (surgery with SRS/SRT, n = 228; SRS/SRT alone, n = 506) from 2011 to 2022 in a retrospective, single-institution cohort. Patients who received upfront whole-brain radiotherapy were excluded. Cox proportional hazards models were constructed for overall survival and additional intracranial outcomes. RESULTS: After adjustment for potential confounders, surgery with postoperative SRS/SRT was associated with decreased all-cause mortality compared with SRS/SRT alone (hazard ratio [HR]: 0.67, 95% CI [0.50-0.89], P = 5.56 × 10 -3 ). The association between surgical resection and overall survival was replicated in a subset of the cohort after cardinality matching (HR: 0.64, 95% CI [0.46-0.88], P = 6.68 × 10 -3 ). Patients with melanoma benefited significantly less from surgical resection compared with patients with other tumor types, most notably non-small-cell lung cancer. Compared with definitive SRS/SRT, cavity SRS/SRT was associated with a significantly reduced risk of both symptomatic radiation necrosis (HR: 0.22, 95% CI [0.08-0.59], P = 2.70 × 10 -3 ) and radiographic radiation necrosis (HR: 0.23, 95% CI [0.09-0.57], P = 1.43 × 10 -3 ) in multivariable models. CONCLUSION: In patients with multiple brain metastases, surgical resection before SRS/SRT is associated with reduced mortality and radiation necrosis. Prospective studies may further delineate patient populations that benefit from aggressive local, brain-directed treatment even with significant intracranial disease burden.

Targeted gene expression profiling predicts meningioma outcomes and radiotherapy responses.

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 < 0.001). The gene expression biomarker identified meningiomas benefiting from postoperative radiotherapy (hazard ratio 0.54, 95% confidence interval 0.37 to 0.78, P = 0.0001) and suggested postoperative management could be refined for 29.8% of patients. In sum, our results identify a targeted gene expression biomarker that improves discrimination of meningioma outcomes, including prediction of postoperative radiotherapy responses.

Trimethylamine N-Oxide and White Matter Hyperintensity Volume Among Patients With Acute Ischemic Stroke.

Importance: Although increasing evidence suggests that trimethylamine N-oxide (TMAO) is associated with atherosclerosis, little is known about whether TMAO and its related metabolites (ie, choline, betaine, and carnitine) are associated with small vessel disease. Objective: To evaluate the association between TMAO and its related metabolites with features of cerebral small vessel disease, including white matter hyperintensity volume (WMHV) and acute lacunar infarction. Design, Setting, and Participants: This cross-sectional study included patients enrolled in the Specialized Programs of Translational Research in Acute Stroke biorepository. The registry included 522 patients with acute ischemic stroke who were 18 years or older who presented at the Massachusetts General Hospital or Brigham and Women's Hospital within 9 hours after onset between January 2007 and April 2010. The analyses in this study were conducted between November 2022 and April 2023. Exposures: Plasma TMAO, choline, betaine, and carnitine were measured by liquid chromatography-tandem mass spectrometry. Main Outcomes and Measures: WMHV was quantified by a semiautomated approach using signal intensity threshold with subsequent manual editing. Ischemic stroke subtype was classified using the Causative Classification System. Results: Among 351 patients included in this study, the mean (SD) age was 69 (15) years; 209 patients (59.5%) were male and had a median (IQR) admission National Institute of Health Stroke Scale of 6 (3-13). The magnetic resonance imaging subgroup consisted of 291 patients with a mean (SD) age of 67 (15) years. Among these, the median (IQR) WMHV was 3.2 (1.31-8.4) cm3. TMAO was associated with WMHV after adjustment for age and sex (ß, 0.15; 95% CI, 0.01-0.29; P < .001). TMAO remained significant in a multivariate analysis adjusted for age, sex, hypertension, diabetes, and smoking (ß, 0.14; 95% CI, 0-0.29; P = .05). TMAO was associated with lacunar stroke but not other ischemic stroke subtypes in a model adjusted for age, sex, hypertension, diabetes, and smoking (OR, 1.67; 95% CI, 1.05-2.66; P = .03). Conclusions and Relevance: In this observational study, TMAO was associated with cerebral small vessel disease determined by WMHV and acute lacunar infarction. The association was independent of traditional vascular risk factors.

Acetylglutamine Differentially Associated with First-Time Versus Recurrent Stroke.

Approximately one-quarter of strokes occur in individuals with prior stroke. Despite the advancement in secondary stroke prevention, the long-term risk of recurrent stroke has remained unchanged. The objective of this study was to identify metabolite risk markers that are associated with recurrent stroke. We performed targeted metabolomic profiling of 162 metabolites by liquid chromatography-tandem mass spectrometry in baseline plasma in a stroke case-cohort study nested within the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, an observational cohort study of 30,239 individuals aged 45 and older enrolled in 2003-2007. Weighted Cox proportional hazard models were used to identify metabolites that had a differential effect on first-time versus recurrent stroke using an interaction term between metabolite and prior stroke at baseline (yes or no). The study included 1391 incident stroke cases identified during 7.1 ± 4.5 years of follow-up and 1050 participants in the random cohort sample. Among 162 metabolites, 13 candidates had a metabolite-by-prior stroke interaction at a p-value <0.05, with one metabolite, acetylglutamine, surpassing the Bonferroni adjusted p-value threshold (p for interaction = 5.78 × 10-5). In an adjusted model that included traditional stroke risk factors, acetylglutamine was associated with recurrent stroke (HR = 2.27 per SD increment, 95% CI = 1.60-3.20, p = 3.52 × 10-6) but not with first-time stroke (HR = 0.96 per SD increment, 95% CI = 0.87-1.06, p = 0.44). Acetylglutamine was associated with recurrent stroke but not first-time stroke, independent of traditional stroke risk factors. Future studies are warranted to elucidate the pathogenesis of acetylglutamine and recurrent stroke risk.

Minimizing Intracranial Disease Before Stereotactic Radiation in Single or Solitary Brain Metastases.

BACKGROUND AND OBJECTIVES: Stereotactic radiotherapy (SRT) in multiple fractions (typically ≤5) can effectively treat a wide range of brain metastases, including those less suitable for single-fraction stereotactic radiosurgery (SRS). Prior prospective studies on surgical resection with stereotactic radiation have focused exclusively on SRS, and retrospective studies have shown equivocal results regarding whether surgery is associated with improved outcomes compared with SRT alone. We compared resection with postoperative cavity SRT or SRS to SRT alone in patients with 1 brain metastasis, while including patients receiving SRS alone as an additional reference group. METHODS: We studied 716 patients in a retrospective, single-institution cohort diagnosed with single or solitary brain metastases from 2007 to 2020. Patients receiving whole-brain radiotherapy were excluded. Cox proportional hazards models were constructed for overall survival and additional intracranial outcomes. RESULTS: After adjustment for potential confounders, surgery with cavity SRT/SRS was associated with decreased all-cause mortality (hazard ratio [HR]: 0.39, 95% CI [0.27-0.57], P = 1.52 × 10 -6 ) compared with SRT alone, along with lower risk of neurological death attributable to intracranial tumor progression (HR: 0.46, 95% CI [0.22-0.94], P = 3.32 × 10 -2 ) and radiation necrosis (HR: 0.15, 95% CI [0.06-0.36], P = 3.28 × 10 -5 ). Surgery with cavity SRS was also associated with decreased all-cause mortality (HR: 0.52, 95% CI [0.35-0.78], P = 1.46 × 10 -3 ), neurological death (HR: 0.30, 95% CI [0.10-0.88], P = 2.88 × 10 -2 ), and radiation necrosis (HR: 0.14, 95% CI [0.03-0.74], P = 2.07 × 10 -2 ) compared with SRS alone. Surgery was associated with lower risk of all-cause mortality and neurological death in cardinality-matched subsets of the cohort. Among surgical patients, gross total resection was associated with extended overall survival (HR: 0.62, 95% CI [0.40-0.98], P = 4.02 × 10 -2 ) along with lower risk of neurological death (HR: 0.31, 95% CI [0.17-0.57], P = 1.84 × 10 -4 ) and local failure (HR: 0.34, 95% CI [0.16-0.75], P = 7.08 × 10 -3 ). CONCLUSION: In patients with 1 brain metastasis, minimizing intracranial disease specifically before stereotactic radiation is associated with improved oncologic outcomes.

Association of Circulating Metabolites With Racial Disparities in Hypertension and Stroke in the REGARDS Study.

BACKGROUND AND OBJECTIVES: In the United States, the risk of stroke is greater among Black compared with that among White individuals. However, the reasons for the difference in stroke incidence are not fully elucidated. We aimed to identify metabolites that account for higher prevalent hypertension and incident ischemic stroke among Black adults. METHODS: We used a stroke case cohort nested within the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. Targeted metabolomic profiling of 162 plasma metabolites was performed by liquid chromatography-tandem mass spectrometry. We identified metabolites that were associated with prevalent hypertension and incident ischemic stroke and mediated the relationship between hypertension and ischemic stroke by weighted logistic regression, Cox proportional hazard model, and inverse odds ratio weighting mediation analysis. RESULTS: Incident ischemic stroke cases adjudicated through April 1, 2019 (n = 1,075) were included in the study. The random cohort sample was derived from the full cohort using stratified sampling (n = 968). Among 162 metabolites, gluconic acid was associated with prevalent hypertension in Black adults (odds ratio [OR] 1.86, 95% CI 1.39-2.47, p = 2.58 × 10-5) but not in White adults (OR 1.00, 95% CI 0.80-1.24, p = 0.97; p for interaction = 4.57 × 10-4). Gluconic acid also demonstrated an association with incident ischemic stroke among Black participants (hazard ratio [HR] 1.53, 95% CI 1.28-1.81, p = 1.76 × 10-6) but not White participants (HR 1.16, 95% CI 1.00-1.34, p = 0.057; p for interaction = 0.019). In mediation analysis, gluconic acid mediated 25.4% (95% CI 4.1%-46.8%, p = 0.02) of the association between prevalent hypertension and incident ischemic stroke among Black individuals. Specific socioeconomic factors were linked to elevated gluconic acid level among Black adults in multivariable analysis, including a Southern dietary pattern (ß = 0.18, 95% CI 0.08-0.28, p < 0.001), lower educational attainment (ß = 0.45, 95% CI 0.19-0.72, p = 0.001), and a lack of exercise (ß = 0.26, 95% CI 0.01-0.51, p = 0.045). DISCUSSION: Gluconic acid is associated with prevalent hypertension and incident ischemic stroke and mediates the relationship between hypertension and ischemic stroke in Black but not White adults. Gluconic acid is a biomarker that is associated with social determinants of health including a Southern diet, low educational attainment, and low physical activity.

Delirium and Previous Psychiatric History Independently Predict Poststroke Posttraumatic Stress Disorder.

OBJECTIVES: Delirium is an acute brain dysfunction that has been correlated with adverse mental health outcomes, such as depression and posttraumatic stress disorder (PTSD). However, delirium has not been studied in relation to mental health outcomes after cerebrovascular events. This study aimed to examine the incidence of PTSD after nontraumatic intracerebral hemorrhage (ICH) and identify new predictors of poststroke PTSD symptoms. METHODS: Clinical data were collected from 205 patients diagnosed with nontraumatic ICH. Demographics and hospital course data were examined. Univariate and multivariable correlational analyses were performed to determine predictors of PTSD symptoms. PTSD symptoms were assessed using PTSD checklist-civilian version (PCL-C) scores. RESULTS: Diagnostic criteria for a positive PTSD screen (PCL-C score ≥44) were met by 13.7%, 20.2%, and 11.6% of nontraumatic patients with ICH at 3, 6, and 12 months, respectively. On univariate analysis, younger age, female sex, unemployed, and in-hospital delirium were correlated with higher PCL-C scores. In multivariable models, younger age, female sex, unemployed, in-hospital delirium, and a previous anxiety or depression diagnosis were associated with higher PCL-C scores at different follow-up times. Modified Rankin Scale scores were also positively correlated with PCL-C scores at each time point. CONCLUSIONS: Delirium, previous psychiatric history, younger age, female sex, and unemployment status were found to be associated with a greater degree of posthemorrhagic stroke PTSD symptoms. More significant PTSD symptoms were also correlated with greater functional impairment. A better understanding of patient susceptibility to PTSD symptoms may help providers coordinate earlier interventions.

Targeted gene expression profiling predicts meningioma outcomes and radiotherapy responses.

Background: Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and current indications for postoperative radiotherapy are controversial. Recent studies have proposed prognostic meningioma classification systems using DNA methylation profiling, copy number variants, DNA sequencing, RNA sequencing, histology, or integrated models based on multiple combined features. Targeted gene expression profiling has generated robust biomarkers integrating multiple molecular features for other cancers, but is understudied for meningiomas. Methods: Targeted gene expression profiling was performed on 173 meningiomas and an optimized gene expression biomarker (34 genes) and risk score (0 to 1) was developed to predict clinical outcomes. Clinical and analytical validation was performed on independent meningiomas from 12 institutions across 3 continents (N = 1856), including 103 meningiomas from a prospective clinical trial. Gene expression biomarker performance was compared to 9 other classification systems. Results: The gene expression biomarker improved discrimination of postoperative meningioma outcomes compared to all other classification systems tested in the independent 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 area under the curve compared to the current standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval [CI] 0.07-0.17, P < 0.001). The gene expression biomarker identified meningiomas benefiting from postoperative radiotherapy (hazard ratio 0.54, 95% CI 0.37-0.78, P = 0.0001) and re-classified up to 52.0% meningiomas compared to conventional clinical criteria, suggesting postoperative management could be refined for 29.8% of patients. Conclusions: A targeted gene expression biomarker improves discrimination of meningioma outcomes compared to recent classification systems and predicts postoperative radiotherapy responses.

Gut microbiota-associated metabolites and risk of ischemic stroke in REGARDS.

Several metabolite markers are independently associated with incident ischemic stroke. However, prior studies have not accounted for intercorrelated metabolite networks. We used exploratory factor analysis (EFA) to determine if metabolite factors were associated with incident ischemic stroke. Metabolites (n = 162) were measured in a case-control cohort nested in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study, which included 1,075 ischemic stroke cases and 968 random cohort participants. Cox models were adjusted for age, gender, race, and age-race interaction (base model) and further adjusted for the Framingham stroke risk factors (fully adjusted model). EFA identified fifteen metabolite factors, each representing a well-defined metabolic pathway. Of these, factor 3, a gut microbiome metabolism factor, was associated with an increased risk of stroke in the base (hazard ratio per one-unit standard deviation, HR = 1.23; 95%CI = 1.15-1.31; P = 1.98 × 10-10) and fully adjusted models (HR = 1.13; 95%CI = 1.06-1.21; P = 4.49 × 10-4). The highest tertile had a 45% increased risk relative to the lowest (HR = 1.45; 95%CI = 1.25-1.70; P = 2.24 × 10-6). Factor 3 was also associated with the Southern diet pattern, a dietary pattern previously linked to increased stroke risk in REGARDS (ß = 0.11; 95%CI = 0.03-0.18; P = 8.75 × 10-3). These findings highlight the role of diet and gut microbial metabolism in relation to incident ischemic stroke.

Integrated molecular and clinical analysis of BRAF-mutant glioma in adults.

BRAF mutations are a significant driver of disease in pediatric low-grade glioma, but the implications of BRAF alterations on the clinical course and treatment response in adult glioma remain unclear. Here, we characterize a multi-institutional cohort of more than 300 patients (>200 adults) with BRAF-mutated glioma using clinical, pathological/molecular, and outcome data. We observed that adult and pediatric BRAF-mutant gliomas harbor distinct clinical and molecular features, with a higher prevalence of BRAFV600E (Class I) and BRAF fusions in pediatric tumors. BRAFV600E alterations were associated with improved survival in adults with glioma overall, though not in glioblastoma. Other genomic alterations observed within functional classes were consistent with the putative roles of those BRAF mutation classes in glioma pathogenesis. In our adult cohort, BRAFV600E alterations conferred sensitivity to targeted therapies. Overall, this large cohort of BRAF-altered adult gliomas demonstrates a broad range of molecular alterations with implications for treatment sensitivity and survival.

Surgical Management in Herpes Simplex Encephalitis: Illustrative Case Report and Systematic Review of the Literature.

BACKGROUND: Herpes simplex virus (HSV) is a common cause of viral encephalitis and can result in refractory seizures. Although HSV encephalitis (HSVE) is treated primarily with acyclovir, surgery can play a role in medically intractable cases. OBJECTIVE: To systematically review cases describing surgery for the treatment of severe HSVE. We also present an illustrative case of anterior temporal lobectomy (ATL) for refractory status epilepticus in a patient with unilateral HSVE. This case demonstrates one clinical context in which surgery can be a useful adjunct. METHODS: We performed a systematic review using PubMed and Google Scholar, including case reports and series describing surgical interventions for HSVE. Clinical data were extracted from 54 publications that incorporated 67 patient cases. RESULTS: Surgical decompression occurred at a wide range of times after the onset of illness, although most patients were operated on 4 or more days after HSVE symptoms began. Numerous reports indicated that decompressive craniectomy, temporal lobectomy, and hematoma removal could treat intractably elevated intracranial pressure because of HSVE with favorable long-term outcomes. We describe an additional case in which a 52-year-old woman with HSVE developed refractory right temporal lobe seizures. After ATL, the seizures resolved with significant clinical improvement. CONCLUSION: Surgical treatment can be a useful adjunct for treatment of HSVE. There is substantial variability in the timing of surgical decompression in patients with HSVE, which can be necessary up to approximately 3 weeks after illness onset. ATL should be considered for refractory status epilepticus in HSVE with a unilateral seizure focus.

Multi-institutional study of the frequency, genomic landscape, and outcome of IDH-mutant glioma in pediatrics.

BACKGROUND: The incidence and biology of IDH1/2 mutations in pediatric gliomas are unclear. Notably, current treatment approaches by pediatric and adult providers vary significantly. We describe the frequency and clinical outcomes of IDH1/2-mutant gliomas in pediatrics. METHODS: We performed a multi-institutional analysis of the frequency of pediatric IDH1/2-mutant gliomas, identified by next-generation sequencing (NGS). In parallel, we retrospectively reviewed pediatric IDH1/2-mutant gliomas, analyzing clinico-genomic features, treatment approaches, and outcomes. RESULTS: Incidence: Among 851 patients with pediatric glioma who underwent NGS, we identified 78 with IDH1/2 mutations. Among patients 0-9 and 10-21 years old, 2/378 (0.5%) and 76/473 (16.1%) had IDH1/2-mutant tumors, respectively. Frequency of IDH mutations was similar between low-grade glioma (52/570, 9.1%) and high-grade glioma (25/277, 9.0%). Four tumors were graded as intermediate histologically, with one IDH1 mutation. Outcome: Seventy-six patients with IDH1/2-mutant glioma had outcome data available. Eighty-four percent of patients with low-grade glioma (LGG) were managed observantly without additional therapy. For low-grade astrocytoma, 5-year progression-free survival (PFS) was 42.9% (95%CI:20.3-63.8) and, despite excellent short-term overall survival (OS), numerous disease-related deaths after year 10 were reported. Patients with high-grade astrocytoma had a 5-year PFS/OS of 36.8% (95%CI:8.8-66.4) and 84% (95%CI:50.1-95.6), respectively. Patients with oligodendroglioma had excellent OS. CONCLUSIONS: A subset of pediatric gliomas is driven by IDH1/2 mutations, with a higher rate among adolescents. The majority of patients underwent upfront observant management without adjuvant therapy. Findings suggest that the natural history of pediatric IDH1/2-mutant glioma may be similar to that of adults, though additional studies are needed.

Plasma Metabolites Link Dietary Patterns to Stroke Risk.

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 (ß = 0.23, 95% confidence interval [CI] [0.14, 0.33], p = 1.14 × 10-6 ), guanosine (ß = -0.13, 95% CI [-0.19, -0.07], p = 6.48 × 10-5 ), gluconic acid (ß = -0.11, 95% CI [-0.18, -0.04], p = 2.06 × 10-3 ), and C7 carnitine (ß = -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.