Faculty Bibliography

Large international consortia examining the genomic architecture of the epilepsies focus on large diagnostic subgroupings such as "all focal epilepsy" and "all genetic generalized epilepsy". In addition, phenotypic data are generally entered into these large discovery databases in a unidirectional manner at one point in time only. However, there are many smaller phenotypic subgroupings in epilepsy, many of which may have unique genomic risk factors. Such a subgrouping or "microphenotype" may be defined as an uncommon or rare phenotype that is well recognized by epileptologists and the epilepsy community, and which may or may not be formally recognized within the International League Against Epilepsy classification system. Here we examine the genetic structure of a number of such microphenotypes and report in particular on two interesting clinical phenotypes, Jeavons syndrome and pediatric status epilepticus. Although no single gene reached exome-wide statistical significance to be associated with any of the diagnostic categories, we observe enrichment of rare damaging variants in established epilepsy genes among Landau-Kleffner patients (GRIN2A) and pediatric status epilepticus patients (MECP2, SCN1A, SCN2A, SCN8A).

OBJECTIVE:This study examined concordance between symptom and performance validity among clinically-referred patients undergoing neuropsychological evaluation for Attention-Deficit/Hyperactivity Disorder (ADHD). METHOD:Data from 203 patients who completed the WAIS-IV Working Memory Index, the Clinical Assessment of Attention Deficit-Adult (CAT-A), and ≥4 criterion performance validity tests (PVTs) were analyzed. RESULTS: CONCLUSION:Symptom and performance invalidity represent dissociable constructs in patients undergoing neuropsychological evaluation of ADHD and should be evaluated independently.

To identify neuroimaging biomarkers of alcohol dependence (AD) from structural magnetic resonance imaging, it may be useful to develop classification models that are explicitly generalizable to unseen sites and populations. This problem was explored in a mega-analysis of previously published datasets from 2,034 AD and comparison participants spanning 27 sites curated by the ENIGMA Addiction Working Group. Data were grouped into a training set used for internal validation including 1,652 participants (692 AD, 24 sites), and a test set used for external validation with 382 participants (146 AD, 3 sites). An exploratory data analysis was first conducted, followed by an evolutionary search based feature selection to site generalizable and high performing subsets of brain measurements. Exploratory data analysis revealed that inclusion of case- and control-only sites led to the inadvertent learning of site-effects. Cross validation methods that do not properly account for site can drastically overestimate results. Evolutionary-based feature selection leveraging leave-one-site-out cross-validation, to combat unintentional learning, identified cortical thickness in the left superior frontal gyrus and right lateral orbitofrontal cortex, cortical surface area in the right transverse temporal gyrus, and left putamen volume as final features. Ridge regression restricted to these features yielded a test-set area under the receiver operating characteristic curve of 0.768. These findings evaluate strategies for handling multi-site data with varied underlying class distributions and identify potential biomarkers for individuals with current AD.

BACKGROUND:Over the past several years there has been increased interest in the use of the Sofia aspiration system (MicroVention, Tustin, California) as a primary aspiration catheter. OBJECTIVE:To perform a multicenter retrospective study examining the efficacy of the Sofia aspiration catheter as a standalone aspiration treatment for large vessel occlusion. METHODS:Consecutive cases in which the Sofia catheter was used for aspiration thrombectomy for large vessel occlusion were included. Exclusion criteria were the following: (1) Sofia not used for first pass, and (2) a stent retriever used as an adjunct on the first pass. The primary outcome of the study was first pass recanalization (Thrombolysis in Cerebral Infarction (TICI) 2c/3). Secondary outcomes included first pass TICI 2b/3, crossover to other thrombectomy devices, number of passes, time from puncture to recanalization, and complications. RESULTS:323 patients were included. First pass TICI 2c/3 was achieved in 49.8% of cases (161/323). First pass TICI 2b/3 was achieved in 69.7% (225/323) of cases. 74.8% had TICI 2b/3 with the Sofia alone. Crossover to other thrombectomy devices occurred in 29.1% of cases (94/323). The median number of passes was 1 (IQR=1-3). Median time from puncture to recanalization was 26 min (IQR=17-45). Procedure related complications occurred in 3.1% (10/323) of cases. CONCLUSION/CONCLUSIONS:Our study highlights the potential advantage of the Sofia aspiration catheter for primary aspiration thrombectomy in acute ischemic stroke. High rates of first pass recanalization with low crossover rates to other thrombectomy devices were achieved. Median procedure time was low, as were procedural complications.

Background/UNASSIGNED:wild-type glioblastoma. Methods/UNASSIGNED:wild-type newly diagnosed and recurrent glioblastoma patients who were treated with laser ablation at 14 US centers between January 2016 and May 2019. Data were monitored for accuracy. Statistical analysis included individual variable summaries, multivariable differences in survival, and median survival numbers. Results/UNASSIGNED:promoter methylation, adjuvant chemotherapy within 12 weeks, and tumor volume <3 cc. Conclusions/UNASSIGNED:wild-type newly diagnosed glioblastoma is comparable to outcomes observed in other tumor resection studies when those patients undergo radiation and chemotherapy following LITT.

The APOE gene is diversified by three alleles ε2, ε3, and ε4 encoding corresponding apolipoprotein (apo) E isoforms. Possession of the ε4 allele is signified by increased risks of age-related cognitive decline, Alzheimer's disease (AD), and the rate of AD dementia progression. ApoE is secreted by astrocytes as high-density lipoprotein-like particles and these are internalized by neurons upon binding to neuron-expressed apoE receptors. ApoE isoforms differentially engage neuronal plasticity through poorly understood mechanisms. We examined here the effects of native apoE lipoproteins produced by immortalized astrocytes homozygous for ε2, ε3, and ε4 alleles on the maturation and the transcriptomic profile of primary hippocampal neurons. Control neurons were grown in the presence of conditioned media from Apoe ^-/- astrocytes. ApoE2 and apoE3 significantly increase the dendritic arbor branching, the combined neurite length, and the total arbor surface of the hippocampal neurons, while apoE4 fails to produce similar effects and even significantly reduces the combined neurite length compared to the control. ApoE lipoproteins show no systemic effect on dendritic spine density, yet apoE2 and apoE3 increase the mature spines fraction, while apoE4 increases the immature spine fraction. This is associated with opposing effects of apoE2 or apoE3 and apoE4 on the expression of NR1 NMDA receptor subunit and PSD95. There are 1,062 genes differentially expressed across neurons cultured in the presence of apoE lipoproteins compared to the control. KEGG enrichment and gene ontology analyses show apoE2 and apoE3 commonly activate expression of genes involved in neurite branching, and synaptic signaling. In contrast, apoE4 cultured neurons show upregulation of genes related to the glycolipid metabolism, which are involved in dendritic spine turnover, and those which are usually silent in neurons and are related to cell cycle and DNA repair. In conclusion, our work reveals that lipoprotein particles comprised of various apoE isoforms differentially regulate various neuronal arbor characteristics through interaction with neuronal transcriptome. ApoE4 produces a functionally distinct transcriptomic profile, which is associated with attenuated neuronal development. Differential regulation of neuronal transcriptome by apoE isoforms is a newly identified biological mechanism, which has both implication in the development and aging of the CNS.

INTRODUCTION/UNASSIGNED:Older adults constitute a large and growing proportion of the population and have unique care needs in the emergency department (ED) setting. The geriatric ED accreditation program aims to improve emergency care provided to older adults by standardizing care provided across accredited geriatric EDs (GED) and through implementation of geriatric-specific care processes. The purpose of this study was to evaluate select care processes at accredited level 1 and level 2 GEDs. METHODS/UNASSIGNED:selected five GED care processes for analysis: initiatives related to delirium, screening for dementia, assessment of function and functional decline, geriatric falls, and minimizing medication-related adverse events. For all protocols, a trained research assistant abstracted information on the tool used or care process, which patients received the interventions, and staff members were involved in the care process; additional information was abstracted specific to individual care processes. RESULTS/UNASSIGNED:A total of 35 level 1 and 2 GEDs were included in this analysis. Among care processes studied, geriatric falls were the most common (31 GEDs, 89%) followed by geriatric pain management (25 GEDs, 71%), minimizing the use of potentially inappropriate medications (24 EDs, 69%), delirium (22 GEDs, 63%), medication reconciliation (21 GEDs, 60%), functional assessment (20 GEDs, 57%), and dementia screening (17 GEDs, 49%). For protocols related to delirium, dementia, function, and geriatric falls, sites used an array of different screening tools and there was heterogeneity in who performed the screening and which patients were assessed. Medication reconciliation protocols leveraged pharmacists, pharmacy technicians and/or nurses. Protocols on avoiding potentially inappropriate medication administration generally focused on ED administration of medications and used the BEERs criteria, and few sites indicated whether pain medications protocols had dosing modifications for age and/or renal function. CONCLUSION/UNASSIGNED:This study provides a snapshot of care processes implemented in level 1 and level 2 accredited GEDs and demonstrates significant heterogeny in how these care processes are implemented.

High co-morbidity and substantial overlap across psychiatric disorders encourage a transition in psychiatry research from categorical to dimensional approaches that integrate neuroscience and psychopathology. Converging evidence suggests that the cerebellum is involved in a wide range of cognitive functions and mental disorders. An important question thus centers on the extent to which cerebellar function can be linked to transdiagnostic dimensions of psychopathology. To address this question, we used a multivariate data-driven statistical technique (partial least squares) to identify latent dimensions linking human cerebellar connectome as assessed by functional MRI to a large set of clinical, cognitive, and trait measures across 198 participants, including healthy controls (n = 92) as well as patients diagnosed with attention-deficit/hyperactivity disorder (n = 35), bipolar disorder (n = 36), and schizophrenia (n = 35). Macroscale spatial gradients of connectivity at voxel level were used to characterize cerebellar connectome properties, which provide a low-dimensional representation of cerebellar connectivity, i.e., a sensorimotor-supramodal hierarchical organization. This multivariate analysis revealed significant correlated patterns of cerebellar connectivity gradients and behavioral measures that could be represented into four latent dimensions: general psychopathology, impulsivity and mood, internalizing symptoms and executive dysfunction. Each dimension was associated with a unique spatial pattern of cerebellar connectivity gradients across all participants. Multiple control analyses and 10-fold cross-validation confirmed the robustness and generalizability of the yielded four dimensions. These findings highlight the relevance of cerebellar connectivity as a necessity for the study and classification of transdiagnostic dimensions of psychopathology and call on researcher to pay more attention to the role of cerebellum in the dimensions of psychopathology, not just within the cerebral cortex.