Unveiling the axonal connectivity between the precuneus and temporal pole: Structural evidence from the cingulum pathways.

Neuroimaging studies have consistently demonstrated concurrent activation of the human precuneus and temporal pole (TP), both during resting-state conditions and various higher-order cognitive functions. However, the precise underlying structural connectivity between these brain regions remains uncertain despite significant advancements in neuroscience research. In this study, we investigated the connectivity of the precuneus and TP by employing parcellation-based fiber micro-dissections in human brains and fiber tractography techniques in a sample of 1065 human subjects and a sample of 41 rhesus macaques. Our results demonstrate the connectivity between the posterior precuneus area POS2 and the areas 35, 36, and TG of the TP via the fifth subcomponent of the cingulum (CB-V) also known as parahippocampal cingulum. This finding contributes to our understanding of the connections within the posteromedial cortices, facilitating a more comprehensive integration of anatomy and function in both normal and pathological brain processes. PRACTITIONER POINTS: Our investigation delves into the intricate architecture and connectivity patterns of subregions within the precuneus and temporal pole, filling a crucial gap in our knowledge. We revealed a direct axonal connection between the posterior precuneus (POS2) and specific areas (35, 35, and TG) of the temporal pole. The direct connections are part of the CB-V pathway and exhibit a significant association with the cingulum, SRF, forceps major, and ILF. Population-based human tractography and rhesus macaque fiber tractography showed consistent results that support micro-dissection outcomes.

Preoperative Frailty Predicts Worse Outcomes after Microvascular Decompression for Trigeminal Neuralgia, Hemifacial Spasm, and Glossopharyngeal Neuralgia: A Multicenter Analysis of 1,473 Patients from a Prospective Surgical Registry.

INTRODUCTION: Microvascular decompression (MVD) is an efficacious neurosurgical intervention for patients with medically intractable neurovascular compression syndromes. However, MVD may occasionally cause life-threatening or altering complications, particularly in patients unfit for surgical operations. Recent literature suggests a lack of association between chronological age and surgical outcomes for MVD. The Risk Analysis Index (RAI) is a validated frailty tool for surgical populations (both clinical and large database). The present study sought to evaluate the prognostic ability of frailty, as measured by RAI, to predict outcomes for patients undergoing MVD from a large multicenter surgical registry. METHODS: The American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP) database (2011-2020) was queried using diagnosis/procedure codes for patients undergoing MVD procedures for trigeminal neuralgia (n = 1,211), hemifacial spasm (n = 236), or glossopharyngeal neuralgia (n = 26). The relationship between preoperative frailty (measured by RAI and 5-factor modified frailty index [mFI-5]) for primary endpoint of adverse discharge outcome (AD) was analyzed. AD was defined as discharge to a facility which was not home, hospice, or death within 30 days. Discriminatory accuracy for prediction of AD was assessed by computation of C-statistics (with 95% confidence interval) from receiver operating characteristic (ROC) curve analysis. RESULTS: Patients undergoing MVD (N = 1,473) were stratified by RAI frailty bins: 71% with RAI 0-20, 28% with RAI 21-30, and 1.2% with RAI 31+. Compared to RAI score 19 and below, RAI 20 and above had significantly higher rates of postoperative major complications (2.8% vs. 1.1%, p = 0.01), Clavien-Dindo grade IV complications (2.8% vs. 0.7%, p = 0.001), and AD (6.1% vs. 1.0%, p < 0.001). The rate of primary endpoint was 2.4% (N = 36) and was positively associated with increasing frailty tier: 1.5% in 0-20, 5.8% in 21-30, and 11.8% in 31+. RAI score demonstrated excellent discriminatory accuracy for primary endpoint in ROC analysis (C-statistic: 0.77, 95% CI: 0.74-0.79) and demonstrated superior discrimination compared to mFI-5 (C-statistic: 0.64, 95% CI: 0.61-0.66) (DeLong pairwise test, p = 0.003). CONCLUSIONS: This was the first study to link preoperative frailty to worse surgical outcomes after MVD surgery. RAI frailty score predicts AD after MVD with excellent discrimination and holds promise for preoperative counseling and risk stratification of surgical candidates. A risk assessment tool was developed and deployed with a user-friendly calculator: https://nsgyfrailtyoutcomeslab.shinyapps.io/microvascularDecompression.

Failure to rescue as a patient safety indicator for neurosurgical patients: are we there yet? A systematic review.

Failure to rescue (FTR) is a standardized patient safety indicator (PSI-04) developed by the Agency for Healthcare Research and Quality (AHRQ) to assess the ability of a healthcare team to prevent mortality following a major complication. However, FTR rates vary and are impacted by non-modifiable individual patient characteristics such as baseline frailty. This raises concerns regarding the validity of FTR as an objective quality metric, as not all patients have the same baseline frailty level, or physiological reserve, to recover from major complications. Literature from other surgical specialties has identified flaws in FTR and called for risk-adjusted metrics. Currently, knowledge of factors influencing FTR and its subsequent implementation in neurosurgical patients are limited. The present review assesses trends in FTR utilization to assess how FTR performs as an objective neurosurgery quality metric. This review then proposes how FTR may be best modified to optimize use in neurosurgical patients. A PubMed search was performed to identify articles published until August 9, 2023. Studies that reported FTR as an outcome in patients undergoing neurosurgical procedures were included. A qualitative assessment was performed using the Newcastle Ottawa Scale (NOS). The initial search revealed 1232 citations. After a title and abstract screen, followed by a full text screen, 12 studies met criteria for inclusion. These articles measured FTR across a total of 764,349 patients undergoing neurosurgical procedures. Five studies analyzed FTR with regard to hospital characteristics, and three studies utilized patient characteristics to predict FTR. All studies were considered high quality based on the NOS. Modifications in criteria to measure FTR are necessary since FTR depends on patient characteristics like frailty. This would allow for the incorporation of risk-adjusted FTR metrics that would aid in clinical decision making in neurosurgical patients.

Preoperative frailty and 30-day mortality after resection of brain metastases: a multicenter surgical registry analysis of 11,038 patients.

OBJECTIVE: Surgery plays a key role in the management of brain metastases. Stratifying surgical risk and individualizing treatment will help optimize outcomes because there is clinical equipoise between radiation and resection as treatment options for many patients. Here, the authors used a multicenter database to assess the prognostic utility of baseline frailty, calculated with the Risk Analysis Index (RAI), for prediction of mortality within 30 days after surgery for brain metastasis. METHODS: The authors pooled patients who had been surgically treated for brain metastasis from the American College of Surgeons National Surgical Quality Improvement Program database (2012-2020). The authors studied the relationship between preoperative calculated RAI score and 30-day mortality after surgery for brain metastasis by using linear-by-linear proportional trend tests and binary logistic regression. The authors calculated C-statistics (with 95% CIs) in receiver operating characteristic (ROC) curve analysis to assess discriminative accuracy. RESULTS: The authors identified 11,038 patients who underwent brain metastasis resection with a median (interquartile range) age of 62 (54-69) years. The authors categorized patients into four groups on the basis of RAI: robust (RAI 0-20), 8.1% of patients; normal (RAI 21-30), 9.2%; frail (RAI 31-40), 75%; and severely frail (RAI ≥ 41), 8.1%. The authors found a positive correlation between 30-day mortality and frailty. RAI demonstrated superior predictive discrimination for 30-day mortality as compared with the 5-factor modified frailty index (mFI-5) on ROC analysis (C-statistic 0.65, 95% CI 0.65-0.66). CONCLUSIONS: The RAI frailty score accurately estimates 30-day mortality after brain metastasis resection and can be calculated online with an open-access software tool: https://nsgyfrailtyoutcomeslab.shinyapps.io/BrainMetsResection/. Accordingly, RAI can be utilized to measure surgical risk, guide treatment options, and optimize outcomes for patients with brain metastases. RAI has superior discrimination for predicting 30-day mortality compared with mFI-5.

Thirty-day outcomes for suboccipital decompression in adults with Chiari malformation type I: a frailty-driven perspective from the American College of Surgeons National Surgical Quality Improvement Program.

OBJECTIVE: When indicated, patients with symptomatic Chiari malformation type I (CM-I) may benefit from suboccipital decompression (SOD). Although SOD is considered a lower-risk neurosurgical procedure, preoperative risk assessment and careful surgical patient selection remain critical. The objectives of the present study were twofold: 1) describe 30-day SOD outcomes for CM patients with attention to the impact of preoperative frailty and 2) design a predictive model for the primary endpoint of nonhome discharge (NHD). METHODS: There were 1015 CM-I patients who underwent SOD in the 2011-2020 American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database, as specified by diagnostic and procedural codes (Current Procedural Terminology code 61343). Descriptive statistics were used to analyze total cohort baseline demographics, preoperative comorbidities, and postoperative outcomes within 30 days of surgery. Univariate cross-tabulation was used to compare baseline demographics and preoperative characteristics across the NHD and home discharge (HD) cohorts. Receiver operating characteristic (ROC) curve analysis was used to assess the discriminative ability of the revised Risk Analysis Index (RAI-rev) on NHD. RESULTS: The study cohort had a median age of 36 years, and 80.6% of patients were female. Race distribution was categorized as White (69.9%), Black (16.6%), and other groups (13.6%). The most common preoperative comorbidities were active smoking (24.4%), hypertension (19.2%), and diabetes mellitus (4.7%). The primary outcome of NHD occurred in 4.6% of patients (n = 47). Increasing frailty (measured by the RAI-rev) was associated with a stepwise increase in the rate of NHD: 2.3% for RAI-rev scores 0-10, 5.8% for RAI-rev scores 11-15, 7.6% for RAI-rev scores 16-20, 18.2% for RAI-rev scores 21-25, and 77.8% for RAI-rev scores ≥ 26 (p < 0.001). Other preoperative factors associated with NHD included older age, nonelective surgery, diabetes, hypertension, and elevated creatinine (all p < 0.01). The other most common 30-day complications included unplanned readmission (9.3%), unplanned reoperation (5.3%), return to the operating room (5.8%), Clavien-Dindo grade IV (life-threatening) (1.5%), organ space surgical site infection (SSI) (1.5%), superficial SSI (1.4%), and reoperation for a CSF leak (1.1%). Surgical mortality (within 30 days) was extremely rare (1/1015, 0.1%). ROC curve analysis demonstrated that RAI-rev predicted NHD with significant discriminatory accuracy among CM-I patients who received SOD treatment (C-statistic 0.731, 95% CI 0.648-0.814). CONCLUSIONS: This decade-long analysis of a multicenter surgical registry provides internationally representative, modern rates of 30-day outcomes after suboccipital decompression (with or without duraplasty) for adult CM-I patients. Preoperative frailty assessment with the RAI-rev may help identify higher-risk surgical candidates.

Frailty as a Superior Predictor of Dysphagia and Surgically Placed Feeding Tube Requirement After Anterior Cervical Discectomy and Fusion Relative to Age.

Frailty is a measure of physiological reserve that has been demonstrated to be a discriminative predictor of worse outcomes across multiple surgical subspecialties. Anterior cervical discectomy and fusion (ACDF) is one of the most common neurosurgical procedures in the United States and has a high incidence of postoperative dysphagia. To determine the association between frailty and dysphagia after ACDF and compare the predictive value of frailty and age. 155,300 patients with cervical stenosis (CS) who received ACDF were selected from the 2016-2019 National Inpatient Sample (NIS) utilizing International Classification of Disease, tenth edition (ICD-10) codes. The 11-point modified frailty index (mFI-11) was used to stratify patients based on frailty: mFI-11 = 0 was robust, mFI-11 = 1 was prefrail, mFI-11 = 2 was frail, and mFI-11 = 3 + was characterized as severely frail. Demographics, complications, and outcomes were compared between frailty groups. A total of 155,300 patients undergoing ACDF for CS were identified, 33,475 (21.6%) of whom were frail. Dysphagia occurred in 11,065 (7.1%) of all patients, and its incidence was significantly higher for frail patients (OR 1.569, p < 0.001). Frailty was a risk factor for postoperative complications (OR 1.681, p < 0.001). Increasing frailty and undergoing multilevel ACDF were significant independent predictors of negative postoperative outcomes, including dysphagia, surgically placed feeding tube (SPFT), prolonged LOS, non-home discharge, inpatient death, and increased total charges (p < 0.001 for all). Increasing mFI-11 score has better prognostic value than patient age in predicting postoperative dysphagia and SPFT after ACDF.

Frailty and outcomes in lacunar stroke.

BACKGROUND: Lacunar strokes (LS) are ischemic strokes of the small perforating arteries of deep gray and white matter of the brain. Frailty has been associated with greater mortality and attenuated response to treatment after stroke. However, the effect of frailty on patients with LS has not been previously described. OBJECTIVE: To analyze the association between frailty and outcomes in LS. METHODS: Patients with LS were selected from the National Inpatient Sample (NIS) 2016-2019 using the International Classification of Disease, 10th edition (ICD-10) diagnosis codes. The 11-point modified frailty scale (mFI-11) was used to group patients into severely frail and non-severely frail cohorts. Demographics, clinical characteristics, and complications were defined. Health care resource utilization (HRU) was evaluated by comparing total hospital charges and length of stay (LOS). Other outcomes studied were discharge disposition and inpatient death. RESULTS: Of 48,980 patients with LS, 10,830 (22.1%) were severely frail. Severely frail patients were more likely to be older, have comorbidities, and pertain to lower socioeconomic status categories. Severely frail patients with LS had worse clinical stroke severity and increased rates of complications such as urinary tract infection (UTI) and pneumonia (PNA). Additionally, severe frailty was associated with unfavorable outcomes and increased HRU. CONCLUSION: Severe frailty in LS patients is associated with higher rates of complications and increased HRU. Risk stratification based on frailty may allow for individualized treatments to help mitigate adverse outcomes in the setting of LS.

Preoperative frailty measured by risk analysis index predicts complications and poor discharge outcomes after Brain Tumor Resection in a large multi-center analysis.

PURPOSE: To evaluate the independent effect of frailty, as measured by the Risk Analysis Index-Administrative (RAI-A) for postoperative complications and discharge outcomes following brain tumor resection (BTR) in a large multi-center analysis. METHODS: Patients undergoing BTR were queried from the National Surgical Quality Improvement Program (NSIQP) for the years 2015 to 2019. Multivariable logistic regression was performed to evaluate the independent associations between frailty tools (age, 5-factor modified frailty score [mFI-5], and RAI-A) on postoperative complications and discharge outcomes. RESULTS: We identified 30,951 patients who underwent craniotomy for BTR; the median age of our study sample was 59 (IQR 47-68) years old and 47.8% of patients were male. Overall, increasing RAI-A score, in an overall stepwise fashion, was associated with increasing risk of adverse outcomes including in-hospital mortality, non-routine discharge, major complications, Clavien-Dindo Grade IV complication, and extended length of stay. Multivariable regression analysis (adjusting for age, sex, BMI, non-elective surgery status, race, and ethnicity) demonstrated that RAI-A was an independent predictor for worse BTR outcomes. The RAI-A tiers 41-45 (1.2% cohort) and > 45 (0.3% cohort) were ~ 4 (Odds Ratio [OR]: 4.3, 95% CI: 2.1-8.9) and ~ 9 (OR: 9.5, 95% CI: 3.9-22.9) times more likely to have in-hospital mortality compared to RAI-A 0-20 (34% cohort). CONCLUSIONS AND RELEVANCE: Increasing preoperative frailty as measured by the RAI-A score is independently associated with increased risk of complications and adverse discharge outcomes after BTR. The RAI-A may help providers present better preoperative risk assessment for patients and families weighing the risks and benefits of potential BTR.

Rapid exponential increase in neurosurgery departmental scholarly output following an intensive research initiative.

There has been extensive research into methods of increasing academic departmental scholarly activity (DSA) through targeted interventions. Residency programmes are responsible for ensuring sufficient scholarly opportunities for residents. We sought to discover the outcomes of an intensive research initiative (IRI) on DSA in our department in a short-time interval. IRI was implemented, consisting of multiple interventions, to rapidly produce an increase in DSA through resident/medical student faculty engagement. We compare pre-IRI (8 years) and post-IRI (2 years) research products (RP), defined as the sum of oral presentations and publications, to evaluate the IRI. The study was performed in 2020. The IRI resulted in an exponential increase in DSA with an annual RP increase of 350% from 2017 (3 RP) to 2018 (14 RP), with another 92% from 2018 (14 RP) to 2019 (27 RP). RP/year exponentially increased from 2.1/year to 10.5/year for residents and 0.5/year to 10/year for medical students, resulting in a 400% and 1900% increase in RP/year, respectively. The common methods in literature to increase DSA included instituting protected research time (23.8%) and research curriculum (21.5%). We share our department's increase in DSA over a short 2-year period after implementing our IRI. Our goal in reporting our experience is to provide an example for departments that need to rapidly increase their DSA. By reporting the shortest time interval to achieve exponential DSA growth, we hope this example can support programmes in petitioning hospitals and medical colleges for academic support resources.

Divergent roles of astrocytic versus neuronal EAAT2 deficiency on cognition and overlap with aging and Alzheimer's molecular signatures.

The excitatory amino acid transporter 2 (EAAT2) is the major glutamate transporter in the brain expressed predominantly in astrocytes and at low levels in neurons and axonal terminals. EAAT2 expression is reduced in aging and sporadic Alzheimer's disease (AD) patients' brains. The role EAAT2 plays in cognitive aging and its associated mechanisms remains largely unknown. Here, we show that conditional deletion of astrocytic and neuronal EAAT2 results in age-related cognitive deficits. Astrocytic, but not neuronal EAAT2, deletion leads to early deficits in short-term memory and in spatial reference learning and long-term memory. Neuronal EAAT2 loss results in late-onset spatial reference long-term memory deficit. Neuronal EAAT2 deletion leads to dysregulation of the kynurenine pathway, and astrocytic EAAT2 deficiency results in dysfunction of innate and adaptive immune pathways, which correlate with cognitive decline. Astrocytic EAAT2 deficiency also shows transcriptomic overlaps with human aging and AD. Overall, the present study shows that in addition to the widely recognized astrocytic EAAT2, neuronal EAAT2 plays a role in hippocampus-dependent memory. Furthermore, the gene expression profiles associated with astrocytic and neuronal EAAT2 deletion are substantially different, with the former associated with inflammation and synaptic function similar to changes observed in human AD and gene expression changes associated with inflammation similar to the aging human brain.

Preoperative risk model for perioperative stroke after intracranial tumor resection: ACS NSQIP analysis of 30,951 cases.

OBJECTIVE: Perioperative and/or postoperative cerebrovascular accidents (PCVAs) after intracranial tumor resection (ITR) are serious complications with devastating effects on quality of life and survival. Here, the authors retrospectively analyzed a prospectively maintained, multicenter surgical registry to design a risk model for PCVA after ITR to support efforts in neurosurgical personalized medicine to risk stratify patients and potentially mitigate poor outcomes. METHODS: The National Surgical Quality Improvement Program database was queried for ITR cases (2015-2019, n = 30,951). Patients with and without PCVAs were compared on baseline demographics, preoperative clinical characteristics, and outcomes. Frailty (physiological reserve for surgery) was measured by the Revised Risk Analysis Index (RAI-rev). Logistic regression analysis was performed to identify independent associations between preoperative covariates and PCVA occurrence. The ITR-PCVA risk model was generated based on logit effect sizes and assessed in area under the receiver operating characteristic curve (AUROC) analysis. RESULTS: The rate of PCVA was 1.7% (n = 532). Patients with PCVAs, on average, were older and frailer, and had increased rates of nonelective surgery, interhospital transfer status, diabetes, hypertension, unintentional weight loss, and elevated BUN. PCVA was associated with higher rates of postoperative reintubation, infection, thromboembolic events, prolonged length of stay, readmission, reoperation, nonhome discharge destination, and 30-day mortality (all p < 0.001). In multivariable analysis, predictors of PCVAs included RAI "frail" category (OR 1.7, 95% CI 1.2-2.4; p = 0.006), Black (vs White) race (OR 1.5, 95% CI 1.1-2.1; p = 0.009), nonelective surgery (OR 1.4, 95% CI 1.1-1.7; p = 0.003), diabetes mellitus (OR 1.5, 95% CI 1.1-1.9; p = 0.002), hypertension (OR 1.4, 95% CI 1.1-1.7; p = 0.006), and preoperative elevated blood urea nitrogen (OR 1.4, 95% CI 1.1-1.8; p = 0.014). The ITR-PCVA predictive model was proposed from the resultant multivariable analysis and performed with a modest C-statistic in AUROC analysis of 0.64 (95% CI 0.61-0.66). Multicollinearity diagnostics did not detect any correlation between RAI-rev parameters and other covariates (variance inflation factor = 1). CONCLUSIONS: The current study proposes a novel preoperative risk model for PCVA in patients undergoing ITR. Patients with poor physiological reserve (measured by frailty), multiple comorbidities, abnormal preoperative laboratory values, and those admitted under high acuity were at highest risk. The ITR-PCVA risk model may support patient-centered counseling striving to respect goals of care and maximize quality of life. Future prospective studies are warranted to validate the ITR-PCVA risk model and evaluate its utility as a bedside clinical tool.

Association of baseline frailty status with clinical outcome following aneurysmal subarachnoid hemorrhage.

OBJECTIVES: Aneurysmal subarachnoid hemorrhage (aSAH) is an emergent neurosurgical condition associated with high morbidity and mortality. The prognostic significance of baseline frailty status in aSAH patients has not been previously evaluated in a large, nationally representative sample. MATERIALS AND METHODS: Clinical outcomes data from the National Inpatient Sample from 2010-2018 were compared among sub-cohorts stratifying admissions by increasing frailty thresholds [(assessed using the 11-point modified frailty index (mFI-11)]. The previously validated NIS-SAH Severity Score (NIS-SSS) and NIS-SAH Outcome Measure (NIS-SOM) were utilized. Complex samples multivariable logistic regression and receiver operating characteristic (ROC) curve analyses were performed to assess adjusted associations and discrimination of frailty for endpoints. RESULTS: Among 64,102 aSAH hospitalizations (mean age 55.4 years), 20.4% of admissions were classified as robust (mFI=0), 43.4% as pre-frail (mFI = 1), 24.9% as frail (mFI = 2), and 11.2% as severely frail (mFI ≥ 3). Following multivariable analysis adjusting for age and aSAH severity, increasing frailty was independently associated with NIS-SOM (OR = 1.15, 95% CI 1.09-1.21; p < 0.001), extended length of hospital stay (eLOS) (OR = 1.08, 1.02-1.13; p = 0.008), neurological complications (OR = 1.08, 1.03-1.13; p < 0.001), and medical complications (OR = 1.14, 1.08-1.21; p < 0.001). Based on ROC curve analysis, frailty achieved an AUC of 0.59 (0.58-0.60) and 0.54 (0.53-0.55) for NIS-SOM and eLOS, respectively. Age and NIS-SSS demonstrated significantly greater discrimination for NIS-SOM [AUC 0.69 (0.68-0.70) and 0.79 (0.78-0.80), respectively), while NIS-SSS achieved significantly greater discrimination for eLOS [(AUC 0.74 (0.73-0.75)] in comparison to both age and frailty. CONCLUSIONS: This national database evaluation of frailty in aSAH patients demonstrates an independent association between increasing frailty and poor functional outcome. Age and aSAH severity, however, may be more robust prognostic factors.

Association of baseline frailty status and age with postoperative morbidity and mortality following intracranial meningioma resection.

PURPOSE: Although numerous studies have established advanced patient age as a risk factor for poor outcomes following intracranial meningioma resection, large-scale evaluation of frailty for preoperative risk assessment has yet to be examined. METHODS: Weighted discharge data from the National Inpatient Sample were queried for adult patients undergoing benign intracranial meningioma resection from 2015 to 2018. Complex samples multivariable logistic regression models and receiver operating characteristic curve analysis were performed to evaluate adjusted associations and discrimination of frailty, quantified using the 11-factor modified frailty index (mFI), for clinical endpoints. RESULTS: Among 20,250 patients identified (mean age 60.6 years), 35.4% (n = 7170) were robust (mFI = 0), 34.5% (n = 6985) pre-frail (mFI = 1), 20.1% (n = 4075) frail (mFI = 2), and 10.0% (n = 2020) severely frail (mFI ≥ 3). On univariable analysis, these sub-cohorts stratified by increasing frailty were significantly associated with the development of Clavien-Dindo grade IV (life-threatening) complications (inclusive of those resulting in mortality) (1.3% vs. 3.1% vs. 6.5% vs. 9.4%, p < 0.001) and extended length of stay (eLOS) (15.4% vs. 22.5% vs. 29.3% vs. 37.4%, p < 0.001). Following multivariable analysis, increasing frailty (aOR 1.40, 95% CI 1.17, 1.68, p < 0.001) and age (aOR 1.20, 95% CI 1.05, 1.38, p = 0.009) were both independently associated with development of life-threatening complications or mortality, whereas increasing frailty (aOR 1.20, 95% CI 1.10, 1.32, p < 0.001), but not age, was associated with eLOS. Frailty (by mFI-11) achieved superior discrimination in comparison to age for both endpoints (AUC 0.69 and 0.61, respectively). CONCLUSION: Frailty may be more accurate than advanced patient age alone for prognostication of adverse events and outcomes following intracranial meningioma resection.

Tau pathology involves protein phosphatase 2A in parkinsonism-dementia of Guam.

Parkinsonism-dementia (PD) of Guam is a neurodegenerative disease with parkinsonism and early-onset Alzheimer-like dementia associated with neurofibrillary tangles composed of hyperphosphorylated microtubule-associated protein, tau. ß-N-methylamino-l-alanine (BMAA) has been suspected of being involved in the etiology of PD, but the mechanism by which BMAA leads to tau hyperphosphorylation is not known. We found a decrease in protein phosphatase 2A (PP2A) activity associated with an increase in inhibitory phosphorylation of its catalytic subunit PP2Ac at Tyr(307) and abnormal hyperphosphorylation of tau in brains of patients who had Guam PD. To test the possible involvement of BMAA in the etiopathogenesis of PD, we studied the effect of this environmental neurotoxin on PP2A activity and tau hyperphosphorylation in mouse primary neuronal cultures and metabolically active rat brain slices. BMAA treatment significantly decreased PP2A activity, with a concomitant increase in tau kinase activity resulting in elevated tau hyperphosphorylation at PP2A favorable sites. Moreover, we found an increase in the phosphorylation of PP2Ac at Tyr(307) in BMAA-treated rat brains. Pretreatment with metabotropic glutamate receptor 5 (mGluR5) and Src antagonists blocked the BMAA-induced inhibition of PP2A and the abnormal hyperphosphorylation of tau, indicating the involvement of an Src-dependent PP2A pathway. Coimmunoprecipitation experiments showed that BMAA treatment dissociated PP2Ac from mGluR5, making it available for phosphorylation at Tyr(307). These findings suggest a scenario in which BMAA can lead to tau pathology by inhibiting PP2A through the activation of mGluR5, the consequent release of PP2Ac from the mGluR5-PP2A complex, and its phosphorylation at Tyr(307) by Src.

Passive immunization targeting the N-terminal projection domain of tau decreases tau pathology and improves cognition in a transgenic mouse model of Alzheimer disease and tauopathies.

Intraneuronal accumulation of abnormally hyperphosphorylated tau in the brain is a histopathological hallmark of Alzheimer's disease and a family of related neurodegenerative disorders collectively called tauopathies. At present there is no effective treatment available for these progressive neurodegenerative diseases which are clinically characterized by dementia in mid to old-age. Here we report the treatment of 14-17-months-old 3xTg-AD mice with tau antibodies 43D (tau 6-18) and 77E9 (tau 184-195) to the N-terminal projection domain of tau or mouse IgG as a control by intraperitoneal injection once a week for 4 weeks, and the effects of the passive immunization on reduction of hyperphosphorylated tau, Aß accumulation and cognitive performance in these animals. We found that treatment with tau antibodies 43D and 77E9 reduced total tau level, decreased tau hyperphosphorylated at Ser199, Ser202/Thr205 (AT8), Thr205, Ser262/356 (12E8), and Ser396/404 (PHF-1) sites, and a trend to reduce Aß pathology. Most importantly, targeting N-terminal tau especially by 43D (tau 6-18) improved reference memory in the Morris water maze task in 3xTg-AD mice. We did not observe any abnormality in general physical characteristics of the treated animals with either of the two antibodies during the course of this study. Taken together, our studies demonstrate for the first time (1) that passive immunization targeting normal tau can effectively clear the hyperphosphorylated protein and possibly reduce Aß pathology from the brain and (2) that targeting N-terminal projection domain of tau containing amino acid 6-18 is especially beneficial. Thus, targeting selective epitopes of N-terminal domain of tau may present a novel effective therapeutic opportunity for Alzheimer disease and other tauopathies.

Disease modifying effect of chronic oral treatment with a neurotrophic peptidergic compound in a triple transgenic mouse model of Alzheimer's disease.

Besides the presence of amyloid beta (Aß) plaques and neurofibrillary tangles, neurogenesis and synaptic plasticity are markedly impaired in Alzheimer's disease (AD) possibly contributing to cognitive impairment. In this context, neurotrophic factors serve as a promising therapeutic approach via utilization of regenerative capacity of brain to shift the balance from neurodegeneration to neural regeneration. However, besides more conventional "bystander" effect, to what extent can neurotrophic compounds affect underlying AD pathology remains questionable. Here we investigated the effect of chronic oral treatment with a ciliary neurotrophic factor (CNTF) derived peptidergic compound, P021 (Ac-DGGL(A)G-NH2), on disease pathology both at moderate and severe stages in a transgenic mouse model of AD. 3xTg-AD and wild type female mice were treated for 12months with P021 or vehicle diet starting at 9-10months of age. A significant reduction in abnormal hyperphosphorylation and accumulation of tau at known major AD neurofibrillary pathology associated sites was observed. The effect of P021 on Aß pathology was limited to a significant decrease in soluble Aß levels and a trend towards reduction in Aß plaque load in CA1 region of hippocampus, consistent with reduction in Aß generation and not clearance. This disease modifying effect was probably via increased brain derived neurotrophic factor (BDNF) expression mediated decrease in glycogen synthase kinase-3-ß (GSK3ß) activity we found in P021 treated 3xTg-AD mice. P021 treatment also rescued deficits in cognition, neurogenesis, and synaptic plasticity in 3xTg-AD mice. These findings demonstrate the potential of the neurotrophic peptide mimetic as a disease modifying therapy for AD.

Frailty as a Predictor of Post-Surgical Outcomes in Patients With Cutaneous Malignancies of the Scalp and Neck Requiring Flap Reconstruction.

BACKGROUND: Investigate the ability of frailty status to predict post-surgical outcomes in patients with cutaneous malignancies of the scalp and neck undergoing flap reconstruction. METHODS: National Surgical Quality Improvement Program database was used to isolate patients with cutaneous malignancies of the scalp and neck who underwent surgical resection between 2015 to 2019. Univariate and multivariate analyses were performed to determine if frailty score correlated with negative post-operative outcomes. Receiver operating characteristic (ROC) curves allowed testing of the discriminative performance of age versus frailty. RESULTS: This study demonstrated an independent correlation between frailty and major complications as well as non-home discharge. In ROC curve analysis, frailty demonstrated superior discrimination compared to age for predicting major complications. CONCLUSION: Our study demonstrated an association between increasing frailty and major complications as well as the likelihood of a non-home discharge. When compared to age, frailty was also shown to be a better predictor of major complications.

The Limited Utility of the Hospital Frailty Risk Score as a Frailty Assessment Tool in Neurosurgery: A Systematic Review.

BACKGROUND AND OBJECTIVES: The Hospital Frailty Risk Score (HFRS) is an International Classification of Disease 10th Revision-based scale that was originally designed for, and validated in, the assessment of patients 75 years or older presenting in an acute care setting. This study highlights central tenets inherent to the concept of frailty; questions the logic behind, and utility of, HFRS' recent implementation in the neurosurgical literature; and discusses why there is no useful role for HFRS as a frailty-based neurosurgical risk assessment (FBNRA) tool. METHODS: The authors performed a systematic review of the literature per Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, including all cranial and spinal studies that used HFRS as their primary frailty tool. Seventeen (N = 17) studies used HFRS to assess frailty's impact on neurosurgical outcomes. Thirteen total journals, 10 of which were neurosurgical journals, including the highest impact factor journals, published the 17 papers. RESULTS: Increasing HFRS score was associated with adverse outcomes, including prolonged length of stay (11 of 17 studies), nonroutine discharge (10 of 17 studies), and increased hospital costs (9 of 17 studies). Four different HFRS studies, of the 17, predicted one of the following 4 adverse outcomes: worse quality of life, worse functional outcomes, reoperation, or in-hospital mortality. CONCLUSION: Despite its rapid acceptance and widespread proliferation through the leading neurosurgical journals, HFRS lacks any conceptual relationship to the frailty syndrome or FBNRA for individual patients. HFRS measures acute conditions using International Classification of Disease 10th Revision codes and awards "frailty" points for symptoms and examination findings unrelated to the impaired baseline physiological reserve inherent to the very definition of frailty. HFRS lacks clinical utility as it cannot be deployed point-of-care at the bedside to risk stratify patients. HFRS has never been validated in any patient population younger than 75 years or in any nonacute care setting. We recommend HFRS be discontinued as an individual FBNRA tool.

Risk Analysis Index and 30-Day Mortality after Brain Tumor Resection: A Multicenter Frailty Analysis of 31,776 Patients from 2012 to 2020.

Introduction The aim of this study was to evaluate the discriminative accuracy of the preoperative Risk Analysis Index (RAI) frailty score for prediction of mortality or transition to hospice within 30 days of brain tumor resection (BTR) in a large multicenter, international, prospective database. Methods Records of BTR patients were extracted from the American College of Surgeons National Surgical Quality Improvement Program (2012-2020) database. The relationship between the RAI frailty scale and the primary end point (mortality or discharge to hospice within 30 days of surgery) was assessed using linear-by-linear proportional trend tests, logistic regression, and receiver operating characteristic (ROC) curve analysis (area under the curve as C-statistic). Results Patients with BTR ( N = 31,776) were stratified by RAI frailty tier: 16,800 robust (52.8%), 7,646 normal (24.1%), 6,593 frail (20.7%), and 737 severely frail (2.3%). The mortality/hospice rate was 2.5% ( n = 803) and was positively associated with increasing RAI tier: robust (0.9%), normal (3.3%), frail (4.6%), and severely frail (14.2%) ( p < 0.001). Isolated RAI was a robust discriminatory of primary end point in ROC curve analysis in the overall BTR cohort (C-statistic: 0.74; 95% confidence interval [CI]: 0.72-0.76) as well as the malignant (C-statistic: 0.74; 95% CI: 0. 67-0.80) and benign (C-statistic: 0.71; 95% CI: 0.70-0.73) tumor subsets (all p < 0.001). RAI score had statistically significantly better performance compared with the 5-factor modified frailty index and chronological age (both p < 0.0001). Conclusions RAI frailty score predicts 30-day mortality after BTR and may be translated to the bedside with a user-friendly calculator ( https://nsgyfrailtyoutcomeslab.shinyapps.io/braintumormortalityRAIcalc/ ). The findings hope to augment the informed consent and surgical decision-making process in this patient population and provide an example for future study designs.