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Open Access Publications from the University of California

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.

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

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.]

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Cover page of ISMRM Clinical Focus Meeting 2023: Imaging the Fire in the Brain.

ISMRM Clinical Focus Meeting 2023: Imaging the Fire in the Brain.

(2025)

Set during the Annual Meeting of the International Society for Magnetic Resonance in Medicine (ISMRM), the Clinical Focus Meeting (CFM) aims to bridge the gap between innovative magnetic resonance imaging (MRI) scientific research and daily patient care. This initiative is dedicated to maximizing the impact of MRI technology on healthcare outcomes for patients. At the 2023 Annual Meeting, clinicians and scientists from across the globe were invited to discuss neuroinflammation from various angles (entitled Imaging the Fire in the Brain). Topics ranged from fundamental mechanisms and biomarkers of neuroinflammation to the role of different contrast mechanisms, including both proton and non-proton techniques, in brain tumors, autoimmune disorders, and pediatric neuroinflammatory diseases. Discussions also delved into how systemic inflammation can trigger neuroinflammation and the role of the gut-brain axis in causing brain inflammation. Neuroinflammation arises from various external and internal factors and serves as a vital mechanism to mitigate tissue damage and provide neuroprotection. Nonetheless, excessive neuroinflammatory responses can lead to significant tissue injury and subsequent neurological impairments. Prolonged neuroinflammation can result in cellular apoptosis and neurodegeneration, posing severe consequences. MRI can be used to visualize these consequences, by detecting blood-brain barrier damage, characterizing brain lesions, quantifying edema, and identifying specific metabolites. It also facilitates monitoring of chronic changes in both the brain and spinal cord over time, potentially leading to better patient outcomes. This paper represents a summary of the 2023 CFM, and is intended to guide the enthusiastic MR user to several key and novel sequences that MRI offers to image pathophysiologic processes underlying acute and chronic neuroinflammation. EVIDENCE LEVEL: 5 TECHNICAL EFFICACY: Stage 3.

Cover page of Stratifying cognitive and behavioral comorbidities in children with new-onset seizures – The influence of sociodemographic disadvantage

Stratifying cognitive and behavioral comorbidities in children with new-onset seizures – The influence of sociodemographic disadvantage

(2025)

Rationale

Children with new-onset epilepsy often experience co-morbid cognitive and behavioral challenges, which can be influenced by Social Determinants Of Health (SDOH) such as household income and parental education level. Although unsupervised machine learning has identified distinct cognitive and behavioral phenotypes at or near diagnosis, the relationship between these clusters remains underexplored. This study aims to examine the relationship between cognitive and behavioral clusters and the impact of SDOH among children with new-onset seizures.

Methods

We recruited 312 children (ages 6-16) within six weeks of their first recognized seizure. Each participant underwent a comprehensive neuropsychological assessment, from which factor analysis identified four primary domains: language, processing speed, executive function, and verbal memory. Parents also completed the Child's Behavior Checklist (CBCL). K-means cluster analysis was applied to the mean factor scores and CBCL T-scores to identify unique clusters. We assessed SDOH factors, including maternal education level, child's race, household income, and parental marital status, along with clinical epilepsy characteristics such as age at seizure onset, seizure frequency/intensity, seizure syndrome, MRI/EEG abnormalities, and neurologic examination findings to distinguish these clusters.

Results

We identified two primary clusters within both cognitive and behavioral scores: Resilient and At-Risk. Children in the Resilient Cognitive Cluster exhibited fewer behavioral problems, while those in the Resilient Behavior Cluster demonstrated higher cognitive performance. Conversely, the At-Risk Cognitive Cluster was associated with greater behavioral problems, and the At-Risk Behavior Cluster correlated with lower cognitive performance. Notably, almost two-thirds of participants showed congruence in clustering, either displaying resilience in both cognition and behavior or vulnerability in both domains. Resilient children exhibited lower levels of sociodemographic disadvantage, whereas those in the At-Risk Clusters faced significant disadvantages. Sociodemographic factors were more pronounced in differentiating clusters compared to traditional clinical epilepsy characteristics.

Conclusions

Among children with new-onset seizures, some display significant resilience to multimorbidities, while others are particularly vulnerable to neurobehavioral challenges, often linked to sociodemographic disadvantages. Future research should explore whether early interventions targeting SDOH can mitigate these risks and improve outcomes for children with new-onset epilepsy.

Cover page of Spatiotemporal perturbations of the plasminogen activation system in a rat model of acute organophosphate intoxication.

Spatiotemporal perturbations of the plasminogen activation system in a rat model of acute organophosphate intoxication.

(2025)

Neuroinflammation is widely posited to be a key pathogenic mechanism linking acute organophosphate (OP)-induced status epilepticus (SE) to persistent brain injury and abnormal electrical activity that contribute to epilepsy and cognitive impairment. The plasminogen activation system (PAS) promotes neuroinflammation in diverse neurological diseases but whether it is activated following acute OP intoxication has yet to be evaluated. To address this data gap, we characterized the spatiotemporal expression patterns of multiple components of the PAS in a rat model of acute intoxication with the OP, diisopropylfluorophosphate (DFP). Adult male Sprague Dawley rats administered DFP (4 mg/kg, sc), atropine sulfate (2 mg/kg, im) and 2-pralidoxime (25 mg/kg, im) went into SE that persisted for hours. One day after acute DFP-induced SE, plasmin activity and protein concentrations of plasminogen activator inhibitor-1 (PAI-1) in the plasma were increased, though not significantly. In contrast, acute DFP intoxication significantly increased brain levels of PAI-1, tissue-type plasminogen activator (tPA), urokinase plasminogen activator (uPA), and transcripts of TGF-β in a time- and region-dependent manner. In the cortex and hippocampus, quantification of PAI-1, tPA, and uPA by ELISA indicated significantly increased levels at 1 day post-exposure (DPE). PAI-1 and uPA returned to control values by 7 DPE while tPA protein remained elevated at 28 DPE. Immunohistochemistry detected elevated PAI-1 expression in the DFP brain up to 28 DPE. Co-localization of PAI-1 with biomarkers of neurons, microglia, and astrocytes demonstrated that PAI-1 localized predominantly to a subpopulation of astrocytes. Cytologically, PAI-1 localized to astrocytic end feet, but not adjacent neurovascular endothelium. Electron microscopy revealed neuronal metabolic stress and neurodegeneration with disruption of adjacent neurovascular units in the hippocampus post-DFP exposure. These data indicate that acute DFP intoxication altered PAS expression in the brain, with aberrant PAI-1 expression in a subset of reactive astrocyte populations.

Cover page of Molecular heterogeneity in human stroke - What can we learn from the peripheral blood transcriptome?

Molecular heterogeneity in human stroke - What can we learn from the peripheral blood transcriptome?

(2025)

Stroke is a multifaceted disease with genetic and environmental components like diet and lifestyle. The central nervous and immune systems display complex interactions, with the peripheral immune response participating in brain injury and repair mechanisms following stroke. The bidirectional communication between the injured brain and peripheral blood presents an opportunity to investigate the molecular changes in the latter. There is substantial heterogeneity in stroke pathogenesis, pathophysiology, comorbidities, and response to treatment and outcome. This is captured and underscored by heterogeneity in the peripheral blood transcriptome. The current review highlights the role of the human peripheral blood transcriptome architecture for molecular phenotyping of different stroke etiologies and comorbidities, and for identifying underlying molecular correlates with clinically important variables and outcomes. Specific transcriptome features can potentially provide targets for clinical translation and for prioritizing genes and pathways for evaluation in experimental models. We also propose an approach to study the patient-specific transcriptional architecture and uncover the combinatorial heterogeneity in altered pathways in stroke patients that can also guide the search for treatment and prevention targets. Deciphering the molecular heterogeneity of stroke in a tissue that can be easily accessed and monitored, such as peripheral blood, may improve clinical trial success.

Cover page of Structural variants linked to Alzheimers disease and other common age-related clinical and neuropathologic traits.

Structural variants linked to Alzheimers disease and other common age-related clinical and neuropathologic traits.

(2025)

BACKGROUND: Alzheimers disease (AD) is a complex neurodegenerative disorder with substantial genetic influence. While genome-wide association studies (GWAS) have identified numerous risk loci for late-onset AD (LOAD), the functional mechanisms underlying most of these associations remain unresolved. Large genomic rearrangements, known as structural variants (SVs), represent a promising avenue for elucidating such mechanisms within some of these loci. METHODS: By leveraging data from two ongoing cohort studies of aging and dementia, the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP), we performed genome-wide association analysis testing 20,205 common SVs from 1088 participants with whole genome sequencing (WGS) data. A range of Alzheimers disease and other common age-related clinical and neuropathologic traits were examined. RESULTS: First, we mapped SVs across 81 AD risk loci and discovered 22 SVs in linkage disequilibrium (LD) with GWAS lead variants and directly associated with the phenotypes tested. The strongest association was a deletion of an Alu element in the 3UTR of the TMEM106B gene, in high LD with the respective AD GWAS locus and associated with multiple AD and AD-related disorders (ADRD) phenotypes, including tangles density, TDP-43, and cognitive resilience. The deletion of this element was also linked to lower TMEM106B protein abundance. We also found a 22-kb deletion associated with depression in ROS/MAP and bearing similar association patterns as GWAS SNPs at the IQCK locus. In addition, we leveraged our catalog of SV-GWAS to replicate and characterize independent findings in SV-based GWAS for AD and five other neurodegenerative diseases. Among these findings, we highlight the replication of genome-wide significant SVs for progressive supranuclear palsy (PSP), including markers for the 17q21.31 MAPT locus inversion and a 1483-bp deletion at the CYP2A13 locus, along with other suggestive associations, such as a 994-bp duplication in the LMNTD1 locus, suggestively linked to AD and a 3958-bp deletion at the DOCK5 locus linked to Lewy body disease (LBD) (P = 3.36 × 10-4). CONCLUSIONS: While still limited in sample size, this study highlights the utility of including analysis of SVs for elucidating mechanisms underlying GWAS loci and provides a valuable resource for the characterization of the effects of SVs in neurodegenerative disease pathogenesis.

Cover page of Allopregnanolone as an Adjunct Therapy to Midazolam is More Effective Than Midazolam Alone in Suppressing Soman-Induced Status Epilepticus in Male Rats.

Allopregnanolone as an Adjunct Therapy to Midazolam is More Effective Than Midazolam Alone in Suppressing Soman-Induced Status Epilepticus in Male Rats.

(2025)

AIMS: Humans and animals acutely intoxicated with the organophosphate soman can develop sustained status epilepticus (SE) that rapidly becomes refractory to benzodiazepines. We compared the antiseizure efficacy of midazolam, a current standard of care treatment for OP-induced SE, versus combined therapy with midazolam and allopregnanolone (ALLO) in a rat model of soman-induced SE. METHODS: Soman-intoxicated male rats with robust seizure behavior and high-amplitude electroencephalographic (EEG) activity were administered midazolam (0.65 mg, i.m.) 20 min after seizure initiation and 10 min later either a second dose of midazolam or ALLO (12 or 24 mg/kg, i.m.). Seizure behavior and EEG were monitored for 4 h after treatment. Brains were collected at the end of the monitoring period for histological analyses. RESULTS: Animals receiving 2 doses of midazolam exhibited persistent SE. Sequential dosing with midazolam followed by ALLO suppressed electrographic seizure activity. The combination therapy also significantly reduced soman-induced neurodegeneration and neuroinflammation compared to 2 doses of midazolam. High but not low dose ALLO was associated with transitory and reversible respiratory compromise during the 1 h period after dosing. CONCLUSIONS: Treatment with midazolam followed by ALLO was more effective than 2 doses of midazolam in suppressing benzodiazepine-refractory, soman-induced SE, and in mitigating its acute neuropathological consequences.

Cover page of Decoding Visual Spatial Attention Control.

Decoding Visual Spatial Attention Control.

(2025)

In models of visual spatial attention control, it is commonly held that top-down control signals originate in the dorsal attention network, propagating to the visual cortex to modulate baseline neural activity and bias sensory processing. However, the precise distribution of these top-down influences across different levels of the visual hierarchy is debated. In addition, it is unclear whether these baseline neural activity changes translate into improved performance. We analyzed attention-related baseline activity during the anticipatory period of a voluntary spatial attention task, using two independent functional magnetic resonance imaging datasets and two analytic approaches. First, as in prior studies, univariate analysis showed that covert attention significantly enhanced baseline neural activity in higher-order visual areas contralateral to the attended visual hemifield, while effects in lower-order visual areas (e.g., V1) were weaker and more variable. Second, in contrast, multivariate pattern analysis (MVPA) revealed significant decoding of attention conditions across all visual cortical areas, with lower-order visual areas exhibiting higher decoding accuracies than higher-order areas. Third, decoding accuracy, rather than the magnitude of univariate activation, was a better predictor of a subjects stimulus discrimination performance. Finally, the MVPA results were replicated across two experimental conditions, where the direction of spatial attention was either externally instructed by a cue or based on the participants free choice decision about where to attend. Together, these findings offer new insights into the extent of attentional biases in the visual hierarchy under top-down control and how these biases influence both sensory processing and behavioral performance.

Cover page of Rare dysfunctional SCN2A variants are associated with malformation of cortical development.

Rare dysfunctional SCN2A variants are associated with malformation of cortical development.

(2025)

OBJECTIVE: SCN2A encodes the voltage-gated sodium (Na+) channel α subunit NaV1.2, which is important for the generation and forward and back propagation of action potentials in neurons. Genetic variants in SCN2A are associated with a spectrum of neurodevelopmental disorders. However, the mechanisms whereby variation in SCN2A leads to disease remains incompletely understood, and the full spectrum of SCN2A-related disorders may not be fully delineated. METHODS: Here, we identified seven de novo heterozygous variants in SCN2A in eight individuals with developmental and epileptic encephalopathy (DEE) accompanied by prominent malformation of cortical development (MCD). We characterized the electrophysiological properties of Na + currents in human embryonic kidney (HEK) cells transfected with the adult (A) or neonatal (N) isoform of wild-type (WT) and variant NaV1.2 using manual and automated whole-cell voltage clamp recording. RESULTS: The neonatal isoforms of all SCN2A variants studied exhibit gain of function (GoF) with a large depolarized shift in steady-state inactivation, creating a markedly enhanced window current common across all four variants tested. Computational modeling demonstrated that expression of the NaV1.2-p.Met1770Leu-N variant in a developing neocortical pyramidal neuron results in hyperexcitability. SIGNIFICANCE: These results support expansion of the clinical spectrum of SCN2A-related disorders and the association of genetic variation in SCN2A with MCD, which suggests previously undescribed roles for SCN2A in fetal brain development.

Cover page of Extreme Tolerance of Nanoparticle-Protein Corona to Ultra-High Abundance Proteins Enhances the Depth of Serum Proteomics.

Extreme Tolerance of Nanoparticle-Protein Corona to Ultra-High Abundance Proteins Enhances the Depth of Serum Proteomics.

(2025)

The serum nanoparticle-protein corona (NPC) provides specific disease information, thus opening a new avenue for high-throughput in-depth proteomics to facilitate biomarker discovery. Yet, little is known about the interactions between NPs and proteins, and its role in enhanced depth of serum proteomics. Herein, a series of protein spike-in experiments are conducted to systematically investigate protein depletion and enrichment during NPC formation. Proteomic depth is serum concentration-dependent, and NPC exhibits powerful tolerance to ultra-high abundant proteins. In addition, protein-protein interactions (PPI), especially those involving albumin, play a pivotal role in promoting proteomic depth. Furthermore, a triple-protein assay is established to interrogate the relationship between protein binding affinity and concentration. NPC formation is a product of balancing binding affinity, concentration, and PPI. Overall, this study elucidates how NPs achieve protein depletion and enrichment for enhanced serum proteomic depth to gain a better understanding of NPC as an essential tool of proteome profiling.