IL-17/CXCL5 signaling within the oligovascular niche mediates human and mouse white matter injury.

Cerebral small vessel disease and brain white matter injury are worsened by cardiovascular risk factors including obesity. Molecular pathways in cerebral endothelial cells activated by chronic cerebrovascular risk factors alter cell-cell signaling, blocking endogenous and post-ischemic white matter repair. Using cell-specific translating ribosome affinity purification (RiboTag) in white matter endothelia and oligodendrocyte progenitor cells (OPCs), we identify a coordinated interleukin-chemokine signaling cascade within the oligovascular niche of subcortical white matter that is triggered by diet-induced obesity (DIO). DIO induces interleukin-17B (IL-17B) signaling that acts on the cerebral endothelia through IL-17Rb to increase both circulating and local endothelial expression of CXCL5. In white matter endothelia, CXCL5 promotes the association of OPCs with the vasculature and triggers OPC gene expression programs regulating cell migration through chemokine signaling. Targeted blockade of IL-17B reduced vessel-associated OPCs by reducing endothelial CXCL5 expression. In multiple human cohorts, blood levels of CXCL5 function as a diagnostic and prognostic biomarker of vascular cognitive impairment.

Distant Pituitary Adenoma Spread: A Systematic Review and Report of 2 Cases.

BACKGROUND: Distant spread of pituitary adenoma outside the sellar/suprasellar region is classified as pituitary carcinoma. Cerebrospinal fluid (CSF)-born spread of pituitary adenoma can occur after tumor cell spillage into the CSF space after surgery, irradiation, or apoplexy and is not necessarily related to intrinsic tumor biology. OBJECTIVE: To systematically review the literature and describe the clinical characteristics and treatment strategies of patients with pituitary carcinomas. We further present 2 cases from our institution. METHODS: A single-center retrospective review of patients with pituitary adenoma spread to distant intracranial locations between 2000 and 2020 was performed. Electronic databases were searched from their inception to May 25, 2021, and studies describing patients with pituitary spread to distant locations were included. RESULTS: Of 1210 pituitary adenoma cases reviewed, 2 (0.16%) showed tumor spread to distant locations. We found 134 additional cases (from 108 published articles) resulting in a total of 136 cases (61.9% were male). The time to tumor spread ranged between 0 and 516 months (median: 96 months). The follow-up duration ranged between 0 and 240 months (median: 11.5 months). All but 2 patients (98.5%) underwent surgical resection before adenoma spread. The 2 exceptions included a patient with evidence of an apoplectic event on autopsy and another patient with leptomeningeal pituitary spread but an unclear history of apoplexy. Elevated tumor markers were not linked to poor outcomes. CONCLUSION: Distant spread of pituitary adenoma may occur after surgery, irradiation, or apoplexy. It is not necessarily associated with a malignant clinical course.

Demographics and Outcomes of Interhospital Transfer Patients Undergoing Intracranial Tumor Resection: A Retrospective Cohort Analysis.

Introduction Interhospital transfer (IHT) contributes to increasing health care costs and typically accounts for increased patient morbidity and mortality compared to non-IHT patients. IHT inefficiencies leave patients vulnerable to delayed care and subsequent poor outcomes. In this study, we investigated factors influencing IHT of patients undergoing intracranial tumor resection (ITR), by comparing the variables distinguishing IHTs from non-IHT patients. Methods We performed a single-center retrospective review comparing IHT and non-IHT patients undergoing ITR from 2016 to 2018. Study variables included age, sex, race, the Milan Complexity Scale (MCS) score, 11-factor modified frailty index (mFI-11), length of stay (LOS), and Clavien-Dindo Score (CDS). Chi-square and Mann-Whitney U tests were used to identify significant differences in these variables between groups, while variables predictive of transfer status were identified using binary logistic regression. Results Data were collected from 219 patients undergoing ITR, with 80 (36.5%) IHT patients overall. The average age was 52 years (SD 18) and 57.7% were men. The MCS score was significantly higher in the IHT group (p = 0.014); however, mFI-11 was not (p = 0.322). The MCS score was predictive of IHT status in regression analysis (OR 1.17, p = 0.034). The IHT patients had a longer LOS (12 days vs 8 days, p = 0.014) with a lower CDS (p = 0.02). Conclusion The transfer patients for intracranial tumor resection had a higher MCS score and thus comprised a more surgically challenging population compared to non-transfer patients. As expected, IHT patients had a longer LOS as they lived further from hospital by definition.

Spine surgery complexity score predicts outcomes in 671 consecutive spine surgery patients.

BACKGROUND: The spine surgery complexity score (SSCS), previously reported by us, is a simple grading system to predict postoperative complications and hospital length of stay (LOS). This scale is based on the technical difficulty of the spinal procedures being performed. METHODS: We performed a retrospective chart review to validate SSCS in 671 consecutive patients undergoing spine procedures at a quaternary academic hospital. RESULTS: The SSCS was predictive of the hospital LOS and postoperative complications (defined by the ClavienDindo score), based on linear regression analysis (P < 0.001 for both). CONCLUSION: Categorizing procedures according to the SSCS may enable neurosurgeons to assess surgical risk and predict longer LOS courses after spine surgery. Thus, it may prove useful in preoperative patient evaluation/ education and determining a prognosis based on surgical complexity.

Demographics and Outcomes of Interhospital Neurosurgical Transfer Patients Undergoing Spine Surgery.

OBJECTIVE: Interhospital patient transfer (IHT) of patients is common and accounts for a significant portion of health care costs, yet the variables driving neurosurgical IHT have not been systematically described. We analyzed variables that distinguished spine surgery patients who underwent IHT from patients who did not undergo IHT to report on the effect of frailty on IHT. METHODS: A retrospective chart review was performed to collect data on consecutive patients undergoing spinal procedures during 2015-2017. IHT patients were identified and compared with non-interhospital patient transfer (n-IHT) patients to identify factors that distinguished the 2 patient groups using multivariate regression analysis. Studied variables included case complexity, frailty (modified frailty index), age, insurance status, and baseline demographic variables. Postoperative outcomes affected by transfer status were identified in binary regression analysis. RESULTS: During 2015-2017, there were 595 n-IHT and 76 IHT spine surgery patients (N = 671). Increased frailty (modified frailty index ≥3; odds ratio = 2.4, P = 0.01) and increased spine surgery complexity (spine surgery complexity score ≥2; odds ratio = 2.57, P = 0.002) were independent risk factors associated with IHT. IHT was an independent risk factor for increased hospital length of stay and increased postoperative complications (Clavien-Dindo scale; P < 0.001). CONCLUSIONS: IHT patients comprise a more frail and surgically complex surgical spine population compared with n-IHT patients. IHT was also an independent risk factor for increased complications and length of stay after spine surgery. Patients' insurance status and age did not distinguish between IHT and n-IHT groups. This is the first report in any specialty to demonstrate increasing frailty is associated with IHT.

Frailty and spontaneous intracerebral hemorrhage: Does the modified frailty index predict mortality?

OBJECTIVE: This study aims to elucidate the impact of frailty on spontaneous intracranial hemorrhage (SICH) patient outcomes in the United States. PATIENTS AND METHODS: This is a single center retrospective chart review of all adult patients (≥18 years old) admitted with a primary diagnosis of SICH due to hypertension, amyloid angiopathy, and coagulopathy from 2014-2017. The studied variables included length of stay, age, sex, ICH score variables, medications, and frailty as measured by the modified Frailty Index (mFI). RESULTS: A total of 240 patients with 248 SICH were included in the analysis. In this study, mFI was not predictive of overall mortality (p = 0.12). To further investigate this issue, patients with ICH scores of 2 or 3 were separately analyzed to assess the impact of mFI on moderate ICH cases. However, mFI was also not associated with increased hospital mortality in moderate ICH cases (p = 0.812). In bivariate Spearman analysis, mFI significantly correlated with several outcome measures including modified Rankin Scale (MRS) at discharge (p = 0.01), but ICH score also correlated with these outcomes (p < 0.001). Although ICH & mFI scores were both predictive of MRS with linear regression, multivariate demonstrated that the ICH score was the only independent risk factor for MRS (p = 0.698, p < 0.001 respectively). CONCLUSION: Frailty, as measured by the mFI, was not an independent risk factor for increased mortality or worse outcomes in SICH patients. This study does not support incorporating the mFI score for SICH patients for prognostication.

An IL-18-centered inflammatory network as a biomarker for cerebral white matter injury.

Chronic systemic sterile inflammation is implicated in the pathogenesis of cerebrovascular disease and white matter injury. Non-invasive blood markers for risk stratification and dissection of inflammatory molecular substrates in vivo are lacking. We sought to identify whether an interconnected network of inflammatory biomarkers centered on IL-18 and all previously associated with white matter lesions could detect overt and antecedent white matter changes in two populations at risk for cerebral small vessel disease. In a cohort of 167 older adults (mean age: 76, SD 7.1, 83 females) that completed a cognitive battery, physical examination, and blood draw in parallel with MR imaging including DTI, we measured cerebral white matter hyperintensities (WMH) and free water (FW). Concurrently, serum levels of a biologic network of inflammation molecules including MPO, GDF-15, RAGE, ST2, IL-18, and MCP-1 were measured. The ability of a log-transformed population mean-adjusted inflammatory composite score (ICS) to associate with MR variables was demonstrated in an age and total intracranial volume adjusted model. In this cohort, ICS was significantly associated with WMH (ß = 0.222, p = 0.013), FW (ß = 0.3, p = 0.01), and with the number of vascular risk factor diagnoses (r = 0.36, p<0.001). In a second cohort of 131 subjects presenting for the evaluation of acute neurologic deficits concerning for stroke, we used serum levels of 11 inflammatory biomarkers in an unbiased principal component analysis which identified a single factor significantly associated with WMH. This single factor was strongly correlated with the six component ICS identified in the first cohort and was associated with WMH in a generalized linear regression model adjusted for age and gender (p = 0.027) but not acute stroke. A network of inflammatory molecules driven by IL-18 is associated with overt and antecedent white matter injury resulting from cerebrovascular disease and may be a promising peripheral biomarker for vascular white matter injury.

Unique Neurosurgical Morbidity and Mortality Conference Characteristics: A Comprehensive Literature Review of Neurosurgical Morbidity and Mortality Conference Practices with Proposed Recommendations.

OBJECTIVE: The aim of the present study was to review the reported data for neurosurgical complication definitions, report the current scales used to classify these complications, and discuss their limitations. METHODS: A systematic review was performed through a PubMed search using predetermined MeSH terms and inclusion criteria. Studies meeting the inclusion criteria were specific to the field of neurosurgery and had presented a unique complication grading scale. RESULTS: A total of 2156 PubMed results matched our predetermined MeSH terms. Of those, 7 met our inclusion criteria. These 7 studies were reported from 2001 to 2019. Of the 7 studies, 4 were applicable to general neurosurgery, 2 to spine surgery, and 1 to neuroendovascular surgery. The scales were based on the therapy needed, predictability and avoidability, survey/consensus of expert judgment, and the underlying cause of an adverse event. None of these studies had considered the complexity of the surgery or the frailty of the patient in the final grading score. CONCLUSIONS: No current standardized neurosurgical complication grade has been used throughout morbidity and mortality conferences. Although scales have been proposed in reported studies, each with their strengths and limitations, none of these has considered surgery complexity or patient frailty and comorbidities. We believe a comprehensive scale is required that includes a preoperative grading system that factors in baseline surgical complexity and patient frailty.

Plasma Lipid Profiling Identifies Biomarkers of Cerebral Microvascular Disease.

Brain-specific sphingolipids (SLs) may serve as effective biomarkers of white matter hyperintensities (WMH). Here, we investigate the efficacy of SLs as a novel fluid-based biomarker to identify WMH reflective of chronic ischemia. Patients presenting to our stroke center for evaluation of acute neurological deficits were enrolled in the Advanced Serum Profiling in Recent Stroke (ASPIRE) study. From this cohort of 202 individuals, 58 patients who underwent an MRI and did not have a clinical stroke event were included in this study. Plasma samples were collected at the time of MRI, and targeted SL profiling was performed by HPLC/tandem mass spectrometry. T2 FLAIR imaging was evaluated for WMH and scored according to the Fazekas scoring (FS) method and manually quantified. Twenty two SLs were definitively identified, consisting of ceramide (Cer) and sphingomyelin (SM) species. Of these, two sphingolipids, SM 38:1 and Cer 34:1, significantly correlated with high FS (r = 0.287, p = 0.029, and r = 0.356, p = 0.006, respectively) and were used in subsequent analysis. SM 38:1 (OR 1.129, 95% CI 1.032, 1.236, p = 0.008) and Cer 34:1 (OR 1.118, 95% CI 1.031, 1.212, p = 0.007), accurately differentiated between FS 0-2 vs. 2.5-6 in regression analysis. A combined lipid score demonstrated fair discrimination in ROC analysis (AUC = 0.729, p = 0.003) and was cross-validated using leave-one-out analysis. Plasma levels of brain-specific SLs may serve as effective biomarkers of subacute white matter disease.

Posttranslational modifications of apolipoprotein A-II proteoforms in type 2 diabetes.

BACKGROUND: Apolipoprotein A-II (apoA-II) is the second most abundant protein in high-density lipoprotein particles. However, it exists in plasma in multiple forms. The effect of diabetes on apoA-II proteoforms is not known. OBJECTIVE: Our objective was to characterize plasma apoA-II proteoforms in participants with and without type 2 diabetes. METHODS: Using a novel mass spectrometric immunoassay, the relative abundance of apoA-II proteoforms was examined in plasma of 30 participants with type 2 diabetes and 25 participants without diabetes. RESULTS: Six apoA-II proteoforms (monomer, truncated TQ monomer, truncated Q monomer, dimer, truncated Q dimer, and truncated 2Qs dimer) and their oxidized proteoforms were identified. The ratios of oxidized monomer and all oxidized proteoforms to the native apoA-II were significantly greater in the diabetic group (P = .004 and P = .005, respectively) compared with the nondiabetic group. CONCLUSION: The relative abundance of oxidized apoA-II is significantly increased in type 2 diabetes.

Association of Serum Docosahexaenoic Acid With Cerebral Amyloidosis.

IMPORTANCE: Higher dietary intake of the essential fatty acid docosahexaenoic (DHA) has been associated with better cognitive performance in several epidemiological studies. Animal and in vitro studies also indicate that DHA prevents amyloid deposition in the brain. OBJECTIVE: To determine the association between serum DHA levels, cerebral amyloidosis, and the volumes of brain areas affected by Alzheimer disease. DESIGN, SETTINGS, AND PARTICIPANTS: Cross-sectional analysis of serum DHA levels together with measures of amyloid deposition (Pittsburgh Compound B index), brain volumes, and neuropsychological testing scores from 61 participants in the Aging Brain Study. The study was conducted between June 2008 and May 2013, and the data were analyzed between October 2015 and April 2016. Linear models were adjusted for age, sex, years of education, and apolipoprotein E status. MAIN OUTCOMES AND MEASURES: Serum DHA levels with cerebral amyloidosis measured using PIB PET. RESULTS: Samples were available from 61 Aging Brain Study participants (41 women and 20 men) who underwent amyloid PET imaging. The mean (SD) age of the participants was 77 (6) years and ranged from 67 to 88 years. Serum DHA levels (percentage of total fatty acids) were 23% lower in participants with cerebral amyloidosis than those without (0.97 vs 1.25, P = .007) and were inversely correlated with brain amyloid load (r = -0.32, P = .01) independent of age, sex, apolipoprotein E genotype, and years of education. Moreover, greater serum DHA levels were positively associated with brain volume in several subregions affected by AD, in particular the left subiculum (r = 0.38, P = .005) and the left entorhinal volumes (r = 0.51, P = .001). Serum DHA levels were also associated with nonverbal memory scores (r = 0.28, P = .03). CONCLUSIONS AND RELEVANCE: In this study, serum DHA levels were associated with pathogenesis of cerebral amyloidosis and with preservation of entorhinal and hippocampal volumes. These findings suggest an important role for DHA metabolism in brain amyloid deposition during the preclinical or early symptomatic stages of Alzheimer disease.