Open Access Policy Deposits

This series is automatically populated with publications deposited by UC Davis School of Medicine Department of Neurology researchers in accordance with the University of California’s open access policies. For more information see Open Access Policy Deposits and the UC Publication Management System.

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Long-term Neurological Outcomes in Adults with Traumatic Intracranial Hemorrhage Admitted to ICU versus Floor

(2015)

Introduction: The objective of this study was to compare long-term neurological outcomes in low-risk patients with traumatic intracranial hemorrhage (tICH) admitted to the ICU (intensive care unit) versus patients admitted to the floor.

Methods: This retrospective study was conducted at a Level 1 trauma center from October 1, 2008, to February 1, 2013. We defined low-risk patients as age less than 65 years, isolated head injury, normal admission mental status, and no shift or swelling on initial head CT (computed tomography). Clinical data were abstracted from a trauma registry and linked to a brain injury database. We compared the Extended Glasgow Outcome Scale (GOS-E) score at six months between patients admitted to the ICU and patients admitted to the floor. We did a risk-adjusted analysis of the influence of floor admission on a normal GOS-E.

Results: We identified 151 patients; 45 (30%) were admitted to the floor and 106 (70%) to the ICU. Twenty-three (51%; 95% CI [36-66%]) patients admitted to the floor and 55 (52%; 95% CI [42-62%]) patients admitted to the ICU had a normal GOS-E. On adjusted analysis; the odds ratio for floor admission was 0.77 (95% CI [0.36-1.64]) for a normal GOS-E at six months.

Conclusion: Long-term neurological outcomes in low-risk patients with tICH were not markedly different between patients admitted to the ICU and those admitted to the floor. However, we were unable to demonstrate non-inferiority on adjusted analysis. Future work aimed at a larger, prospective cohort may better evaluate the relative impacts of admission type on outcomes. [West J Emerg Med. 2015;16(2):284–290.]

2 supplemental files

Cover page of A Robust ROS Generation and Ferroptotic Lipid Modulation Nanosystem for Mutual Reinforcement of Ferroptosis and Cancer Immunotherapy.

A Robust ROS Generation and Ferroptotic Lipid Modulation Nanosystem for Mutual Reinforcement of Ferroptosis and Cancer Immunotherapy.

(2024)

Ferroptosis initiation is often utilized for synergistic immunotherapy. While, current immunotherapy is limited by an immunosuppressive tumor microenvironment (TME), and ferroptosis is limited by insufficient reactive oxygen species (ROS) and ferroptotic lipids in tumor cells. Here, an arachidonic acid (AA) loaded nanosystem (CTFAP) is developed to mutually reinforce ferroptosis and cancer immunotherapy by augmenting ROS generation and modulating ferroptotic lipids. CTFAP is composed of acid-responsive core calcium peroxide (CaO2) nanoparticles, ferroptotic lipids sponsor AA, tetracarboxylic porphyrin (TCPP) and Fe3+ based metal-organic framework structure, and biocompatible mPEG-DSPE for improved stability. Once endocytosed by tumor cells, CTFAP can release oxygen (O2) and hydrogen peroxide (H2O2) in the acidic TME, facilitating TCPP-based sonodynamic therapy and Fe3+-mediated Fenton-like reactions to generate substantial ROS for cell ferroptosis initiation. The immunogenic cell death (ICD) after ferroptosis promotes interferon γ (IFN-γ) secretion to up-regulate the expression of long-chain family member 4 (ACSL4), cooperating with the released AA from CTFAP to accelerate the accumulation of lipid peroxidation (LPO) and thereby promoting ferroptosis in cancer cells.CTFAP with ultrasound treatment efficiently suppresses tumor growth, has great potential to challenges in cancer immunotherapy.

Sex differences in interacting genetic and functional connectivity biomarkers in Alzheimer’s disease

(2024)

As of 2023, it is estimated that 6.7 million individuals in the United States live with Alzheimer's disease (AD). Prior research indicates that AD disproportionality affects females; females have a greater incidence rate, perform worse on a variety of neuropsychological tasks, and have greater total brain atrophy. Recent research shows that hippocampal functional connectivity differs by sex and may be related to the observed sex differences in AD, and apolipoprotein E (ApoE) ε4 carriers have reduced hippocampal functional connectivity. The purpose of this study was to determine if the ApoE genotype plays a role in the observed sex differences in hippocampal functional connectivity in Alzheimer's disease. The resting state fMRI and T2 MRI of individuals with AD (n = 30, female = 15) and cognitively normal individuals (n = 30, female = 15) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were analyzed using the functional connectivity toolbox (CONN). Our results demonstrated intrahippocampal functional connectivity differed between those without an ε4 allele and those with at least one ε4 allele in each group. Additionally, intrahippocampal functional connectivity differed only by sex when Alzheimer's participants had at least one ε4 allele. These results improve our current understanding of the role of the interacting relationship between sex, ApoE genotype, and hippocampal function in AD. Understanding these biomarkers may aid in the development of sex-specific interventions for improved AD treatment.

Cover page of Metabolomic Profiling and Machine Learning Models for Tumor Classification in Patients with Recurrent IDH-Wild-Type Glioblastoma: A Prospective Study.

Metabolomic Profiling and Machine Learning Models for Tumor Classification in Patients with Recurrent IDH-Wild-Type Glioblastoma: A Prospective Study.

(2024)

BACKGROUND/OBJECTIVES: The recurrence of glioblastoma is an inevitable event in this diseases course. In this study, we sought to identify the metabolomic signature in patients with recurrent glioblastomas undergoing surgery and radiation therapy. METHODS: Blood samples collected prospectively from six patients with recurrent IDH-wildtype glioblastoma who underwent one surgery at diagnosis and a second surgery at relapse were analyzed using untargeted gas chromatography-time-of-flight mass spectrometry to measure metabolite abundance. The data analysis techniques included univariate analysis, correlation analysis, and a sample t-test. For predictive modeling, machine learning (ML) algorithms such as multinomial logistic regression, gradient boosting, and random forest were applied to predict the classification of samples in the correct treatment phase. RESULTS: Comparing samples after the first surgery and after the relapse surgeries to the pre-operative samples showed a significant decrease in sorbitol and mannitol; there was a significant increase in urea, oxoproline, glucose, and alanine. After chemoradiation, two metabolites, erythritol and 6-deoxyglucitol, showed a decrease, with a cut-off of three and a significant reduction for 6-deoxyglucitol, while 2,4-difluorotoluene and 9-myristoleate showed an increase post radiation, with a fold-change cut-off of three. The gradient-boosting ML model achieved a high performance for the prediction of tumor conditions in patients with glioblastoma who had undergone relapse surgery. CONCLUSIONS: We developed an ML predictor for tumor phase based on the plasma metabolomic profile. Our study suggests the potential of combining metabolomics with ML as a new tool to stratify the risk of tumor progression in patients with glioblastoma.

Isolation of psychedelic-responsive neurons underlying anxiolytic behavioral states

(2024)

Psychedelics hold promise as alternate treatments for neuropsychiatric disorders. However, the neural mechanisms by which they drive adaptive behavioral effects remain unclear. We isolated the specific neurons modulated by a psychedelic to determine their role in driving behavior. Using a light- and calcium-dependent activity integrator, we genetically tagged psychedelic-responsive neurons in the medial prefrontal cortex (mPFC) of mice. Single-nucleus RNA sequencing revealed that the psychedelic drove network-level activation of multiple cell types beyond just those expressing 5-hydroxytryptamine 2A receptors. We labeled psychedelic-responsive mPFC neurons with an excitatory channelrhodopsin to enable their targeted manipulation. We found that reactivation of these cells recapitulated the anxiolytic effects of the psychedelic without driving its hallucinogenic-like effects. These findings reveal essential insight into the cell-type-specific mechanisms underlying psychedelic-induced behavioral states.

Cover page of Gender differences in the association between education and late‐life cognitive function in the LifeAfter90 Study: A multiethnic cohort of the oldest–old

Gender differences in the association between education and late‐life cognitive function in the LifeAfter90 Study: A multiethnic cohort of the oldest–old

(2024)

Introduction

Few studies have examined the relationship between education and cognition among the oldest-old.

Methods

Cognitive assessments were conducted biannually for 803 participants (62.6% women) of LifeAfter90, a longitudinal study of individuals ≥ 90 years old. Gender differences in associations between education (< high school, high school, some college, and ≥ college) and cognition (verbal episodic memory, semantic memory, and executive function) were examined at baseline and longitudinally using linear mixed models.

Results

Higher education levels were associated with better cognitive performance at baseline for both men and women. College completion was more strongly associated with better baseline executive function among women. Education-cognition associations for baseline verbal episodic memory and baseline semantic memory did not differ by gender. Education was not associated with a decline in any domain-specific cognitive scores, regardless of gender.

Discussion

Education is associated with cognitive function among the oldest-old and varies by gender and cognitive domain at baseline but not over time.

Highlights

In the oldest-old, higher education was associated with better cognitive function. College completion was more strongly associated with executive function in women. Education was not associated with cognitive decline after age 90 regardless of gender. Improving education could decrease gaps in cognitive level among older individuals.

Long‐term characterization of behavior phenotypes in children with seizures: Analytic approach matters

(2024)

Objective

Behavioral problems in children with new onset epilepsies have been well established in the literature. More recently, the literature indicates the presence of unique behavioral patterns or phenotypes in youth with epilepsy that vary significantly in vulnerability and resilience to behavioral problems. This study contrasts the interpretation of behavioral risk as inferred from cross-sectional versus latent group analytic perspectives, as well as the presence, consistency, stability, and progression of behavioral phenotypes in youth with new onset epilepsy and sibling controls over 3 years.

Methods

Three hundred twelve participants (6-16 years old) were recruited within 6 weeks of their first recognized seizure along with 223 unaffected siblings. Each child's behavior was recorded by parents and teachers frequently over 36 months using the Child Behavior Checklist (CBCL), and each child completed self-report measures of depression symptoms over 36 months. Measures were evaluated cross-sectionally and longitudinally to identify clusters with prototypical behavioral trajectories.

Results

Cross-sectional analyses exhibited a pattern of generalized and undifferentiated behavioral problems compared to sibling controls at baseline and prospectively. In contrast, latent trajectory modeling identified three distinct behavior phenotype clusters across all raters (parents, teachers, and youth) over baseline and longitudinal assessments. CBCL Cluster 1 (~30% of youth with epilepsy) exhibited behavior similar to/better than controls, Cluster 2 (~50%) exhibited moderate behavior issues, and Cluster 3 (~20%) exhibited the most pronounced/problematic behavior, falling into Achenbach's clinically relevant behavior range. Behavior within clusters remained stable and consistent. Teachers' and children's behavior assessments corresponded to these cluster groupings consistently over 36 months. Predictors of cluster membership include seizure syndrome type and social determinants of health.

Significance

This study demonstrates the varying public health perspectives of behavioral risk in youth with epilepsy that result as a function of analytic approach as well as the presence of distinct latent behavioral trajectory phenotypes over time in youth with new onset epilepsy.

Implementation and validation of face de-identification (de-facing) in ADNI4.

(2024)

INTRODUCTION: Recent technological advances have increased the risk that de-identified brain images could be re-identified from face imagery. The Alzheimers Disease Neuroimaging Initiative (ADNI) is a leading source of publicly available de-identified brain imaging, who quickly acted to protect participants privacy. METHODS: An independent expert committee evaluated 11 face-deidentification (de-facing) methods and selected four for formal testing. RESULTS: Effects of de-facing on brain measurements were comparable across methods and sufficiently small to recommend de-facing in ADNI. The committee ultimately recommended mri_reface for advantages in reliability, and for some practical considerations. ADNI leadership approved the committees recommendation, beginning in ADNI4. DISCUSSION: ADNI4 de-faces all applicable brain images before subsequent pre-processing, analyses, and public release. Trained analysts inspect de-faced images to confirm complete face removal and complete non-modification of brain. This paper details the history of the algorithm selection process and extensive validation, then describes the production workflows for de-facing in ADNI. HIGHLIGHTS: ADNI is implementing de-facing of MRI and PET beginning in ADNI4. De-facing alters face imagery in brain images to help protect privacy. Four algorithms were extensively compared for ADNI and mri_reface was chosen. Validation confirms mri_reface is robust and effective for ADNI sequences. Validation confirms mri_reface negligibly affects ADNI brain measurements.

Impaired kidney function, cerebral small vessel disease and cognitive disorders: the Framingham Heart Study

(2024)

Background and hypothesis

It remains unclear whether the relation of chronic kidney disease (CKD) with cognitive dysfunction is independent of blood pressure (BP). We evaluated kidney function in relation to premorbid BP measurements, cerebral small vessel disease (CSVD), and incident mild cognitive impairment (MCI) and dementia in Framingham Offspring Cohort participants.

Methods

We included Framingham Offspring participants free of dementia, attending an examination during midlife (exam cycle 6, baseline) for ascertainment of kidney function status, with brain magnetic resonance imaging late in life (exam cycles 7-9), cognitive outcome data, and available interim hypertension and BP assessments. We related CKD (estimated glomerular filtration rate <60 ml/min/1.73 m2) and albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g) to CSVD markers and cognitive outcomes using multivariable regression analyses.

Results

Among 2604 participants (mean age 67.4 ± 9.2, 64% women, 7% had CKD, and 9% albuminuria), albuminuria was independently associated with covert infarcts [adjusted OR, 1.55 (1.00-2.38); P = 0.049] and incident MCI and dementia [adjusted hazard ratio (HR), 1.68 (1.18-2.41); P = 0.005 and 1.71, (1.11-2.64); P = 0.015, respectively]. CKD was not associated with CSVD markers but was associated with a higher risk of incident dementia [HR, 1.53 (1.02-2.29); P = 0.041]. While albuminuria was predictive of the Alzheimer's disease subtype [adjusted HR = 1.68, (1.03-2.74); P = 0.04), CKD was predictive of vascular dementia [adjusted HR, 2.78 (1.16-6.68); P = 0.023].

Conclusions

Kidney disease was associated with CSVD and cognitive disorders in asymptomatic community dwelling participants. The relation was independent of premorbid BP, suggesting that the link between kidney and brain disease may involve additional mechanisms beyond BP-related injury.