WashU weekly Neuroscience publications

Diffusion basis spectrum imaging provides insights into MS pathology
(2020) Neurology(R) Neuroimmunology & Neuroinflammation, 7 (2), . 

Sun, P., George, A., Perantie, D.C., Trinkaus, K., Ye, Z., Naismith, R.T., Song, S.-K., Cross, A.H.

From the Radiology (P.S., A.G., Z.Y., S.-K.S.), Washington University in Saint Louis, MO; Neurology (D.C.P., R.T.N., A.H.C.), Washington University in Saint Louis, MO; and Biostatistics Shared Resource (K.T.), Washington University in Saint Louis, Siteman Cancer Center, Washington University School of Medicine, St Louis, MO

Abstract
OBJECTIVE: To use diffusion basis spectrum imaging (DBSI) to assess how damage to normal-appearing white matter (NAWM) in the corpus callosum (CC) influences neurologic impairment in people with MS (pwMS). METHODS: Using standard MRI, the primary pathologies in MS of axonal injury/loss, demyelination, and inflammation are not differentiated well. DBSI has been shown in animal models, phantoms, and in biopsied and autopsied human CNS tissues to distinguish these pathologies. Fifty-five pwMS (22 relapsing-remitting, 17 primary progressive, and 16 secondary progressive) and 13 healthy subjects underwent DBSI analyses of NAWM of the CC, the main WM tract connecting the cerebral hemispheres. Tract-based spatial statistics were used to minimize misalignment. Results were correlated with scores from a battery of clinical tests focused on deficits typical of MS. RESULTS: Normal-appearing CC in pwMS showed reduced fiber fraction and increased nonrestricted isotropic fraction, with the most extensive abnormalities in secondary progressive MS (SPMS). Reduced DBSI-derived fiber fraction and increased DBSI-derived nonrestricted isotropic fraction of the CC correlated with worse cognitive scores in pwMS. Increased nonrestricted isotropic fraction in the body of the CC correlated with impaired hand function in the SPMS cohort. CONCLUSIONS: DBSI fiber fraction and nonrestricted isotropic fraction were the most useful markers of injury in the NAWM CC. These 2 DBSI measures reflect axon loss in animal models. Because of its ability to reveal axonal loss, as well as demyelination, DBSI may be a useful outcome measure for trials of CNS reparative treatments. Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

A narrative review of electroencephalogram-based monitoring during cardiovascular surgery
(2020) Current Opinion in Anaesthesiology, 33 (1), pp. 92-100. 

Kaiser, H.A.^a , Hight, D.^a , Avidan, M.S.^b

^a Department of Anaesthesiology and Pain Medicine, University Hospital Bern, Inselspital, Bern, Switzerland
^b Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Purpose of reviewThe current narrative review focuses on depth of hypnosis monitoring with electroencephalography (EEG) during cardiovascular surgery. There have been important findings in recent years regarding the challenges and limitations of EEG-based monitoring during general anesthesia. The purpose of this review is to summarize key EEG-related concepts, as well as to highlight some of the advantages and disadvantages of processed and unprocessed EEG monitoring, especially for older patients with comorbidities undergoing cardiovascular surgery.Recent findingsThe brain is the target organ of anesthesia. Using the EEG or processed EEG to guide anesthetic administration during cardiovascular surgery conceptually allows precision patient-centered anesthesia. It is suggested that inadequate anesthesia, with the possibility of traumatic intraoperative awareness, can potentially be avoided. Furthermore, excessive anesthesia, with hemodynamic compromise and theoretical risk of delirium, can be minimized. Frail, older patients undergoing major surgery with preexisting neurocognitive disorders might be especially vulnerable to perioperative neurological and other complications. Tailoring anesthetic administration, based on individual patient needs partly guided by certain EEG features, might yield improved perioperative outcomes.SummaryAbility to interpret the EEG during surgery might help anesthesia clinicians to individualize anesthetic administration to prevent adverse events, and optimize postoperative recovery. © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Author Keywords
awareness;  cardiovascular anesthesia;  delirium;  electroencephalogram;  intraoperative monitoring

Document Type: Review
Publication Stage: Final
Source: Scopus

Pediatric Neurocritical Care: From Field to Follow-Up
(2020) Pediatric Neurology, . 

Guerriero, R.M.^a , Guilliams, K.P.^{a b}

^a Department of Neurology, Division of Pediatric and Developmental Neurology, St. Louis, MO, United States
^b Department of Pediatrics, Division of Critical Care, Washington University School of Medicine in St. Louis, St. Louis, MO, United States

Document Type: Editorial
Publication Stage: Article in Press
Source: Scopus

Refining Indications for the Supercharge End-to-Side Anterior Interosseous to Ulnar Motor Nerve Transfer in Cubital Tunnel Syndrome
(2020) Plastic and Reconstructive Surgery, 145 (1), pp. 106e-116e. 

Power, H.A., Kahn, L.C., Patterson, M.M., Yee, A., Moore, A.M., Mackinnon, S.E.

Edmonton, Alberta, Canada; St. Louis, Mo.; and Chapel Hill, N.C. From the Division of Plastic Surgery, University of Alberta; the Milliken Hand Rehabilitation Center, Department of Occupational Therapy, and the Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine; and the Department of Orthopedic Surgery, University of North Carolina

Abstract
The supercharge end-to-side anterior interosseous to ulnar motor nerve transfer has gained popularity over the past decade as a method of augmenting intrinsic muscle reinnervation in patients with acute neurotmetic ulnar nerve injuries. Controversy remains regarding its efficacy and appropriate clinical indications in cubital tunnel syndrome, where the timing of onset of axonal loss is less clear. The authors present guidelines for patient selection, surgical technique, and postoperative rehabilitation based on their clinical experience with the technique in this patient population. CLINICAL QUESTION/LEVEL OF EVIDENCE:: Therapeutic, V.

Document Type: Article
Publication Stage: Final
Source: Scopus

Cellular and molecular characterization of multiplex autism in human induced pluripotent stem cell-derived neurons
(2019) Molecular Autism, 10 (1), art. no. 51, . 

Lewis, E.M.A.^a , Meganathan, K.^a , Baldridge, D.^b , Gontarz, P.^a , Zhang, B.^a , Bonni, A.^c , Constantino, J.N.^d , Kroll, K.L.^a

^a Department of Developmental Biology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, United States
^b Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, United States
^c Department of Neuroscience, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, United States
^d Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, United States

Abstract
Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with pronounced heritability in the general population. This is largely attributable to the effects of polygenic susceptibility, with inherited liability exhibiting distinct sex differences in phenotypic expression. Attempts to model ASD in human cellular systems have principally involved rare de novo mutations associated with ASD phenocopies. However, by definition, these models are not representative of polygenic liability, which accounts for the vast share of population-attributable risk. Methods: Here, we performed what is, to our knowledge, the first attempt to model multiplex autism using patient-derived induced pluripotent stem cells (iPSCs) in a family manifesting incremental degrees of phenotypic expression of inherited liability (absent, intermediate, severe). The family members share an inherited variant of uncertain significance (VUS) in GPD2, a gene that was previously associated with developmental disability but here is insufficient by itself to cause ASD. iPSCs from three first-degree relatives and an unrelated control were differentiated into both cortical excitatory (cExN) and cortical inhibitory (cIN) neurons, and cellular phenotyping and transcriptomic analysis were conducted. Results: cExN neurospheres from the two affected individuals were reduced in size, compared to those derived from unaffected related and unrelated individuals. This reduction was, at least in part, due to increased apoptosis of cells from affected individuals upon initiation of cExN neural induction. Likewise, cIN neural progenitor cells from affected individuals exhibited increased apoptosis, compared to both unaffected individuals. Transcriptomic analysis of both cExN and cIN neural progenitor cells revealed distinct molecular signatures associated with affectation, including the misregulation of suites of genes associated with neural development, neuronal function, and behavior, as well as altered expression of ASD risk-associated genes. Conclusions: We have provided evidence of morphological, physiological, and transcriptomic signatures of polygenic liability to ASD from an analysis of cellular models derived from a multiplex autism family. ASD is commonly inherited on the basis of additive genetic liability. Therefore, identifying convergent cellular and molecular phenotypes resulting from polygenic and monogenic susceptibility may provide a critical bridge for determining which of the disparate effects of rare highly deleterious mutations might also apply to common autistic syndromes. © 2019 The Author(s).

Author Keywords
Cortical excitatory neurons;  Cortical inhibitory neurons;  Gene networks;  iPSC modeling;  Multiplex autism;  Neurodevelopment;  Transcriptomics

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Comparing sensitivity to change using the 6-item versus the 17-item Hamilton depression rating scale in the GUIDED randomized controlled trial
(2019) BMC Psychiatry, 19 (1), art. no. 420, . 

Dunlop, B.W.^a , Parikh, S.V.^b , Rothschild, A.J.^c , Thase, M.E.^d , Debattista, C.^e , Conway, C.R.^f , Forester, B.P.^g , Mondimore, F.M.^h , Shelton, R.C.ⁱ , Macaluso, M.^j , Logan, J.^l , Traxler, P.^k , Li, J.^k , Johnson, H.^k , Greden, J.F.^b

^a Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 12 Executive Park Dr. NE, 3rd Floor, Atlanta, GA 30329, United States
^b Department of Psychiatry, National Network of Depression Centers, University of Michigan, Comprehensive Depression Center, Ann Arbor, MI, United States
^c UMass Memorial Healthcare, University of Massachusetts Medical School, Worcester, MA, United States
^d Corporal Michael Crescenz VAMC, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^e Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States
^f Department of Psychiatry, John Cochran Veteran’s Administration Hospital, Washington University School of Medicine, St. Louis, MO, United States
^g McLean Hospital, Division of Geriatric Psychiatry, Harvard Medical School, Belmont, MA, United States
^h Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States
ⁱ Department of Psychiatry, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
^j Department of Psychiatry and Behavioral Sciences, University of Kansas School of Medicine-Wichita, Wichita, KS, United States
^k Assurex Health Inc., Myriad Neuroscience, Mason, OH, United States
^l Myriad Genetics Inc., Salt Lake City, UT, United States

Abstract
Background: Previous research suggests that the 17-item Hamilton Depression Rating Scale (HAM-D17) is less sensitive in detecting differences between active treatment and placebo for major depressive disorder (MDD) than is the HAM-D6 scale, which focuses on six core depression symptoms. Whether HAM-D6 shows greater sensitivity when comparing two active MDD treatment arms is unknown. Methods: This post hoc analysis used data from the intent-to-treat (ITT) cohort (N = 1541) of the Genomics Used to Improve DEpression Decisions (GUIDED) trial, a rater- A nd patient-blinded randomized controlled trial. GUIDED compared combinatorial pharmacogenomics-guided care with treatment as usual (TAU) in patients with MDD. Percent of symptom improvement, response rate and remission rate from baseline to week 8 were evaluated using both scales. Analyses were performed for the full cohort and for the subset of patients who at baseline were taking medications predicted by the test to have moderate or significant gene-drug interactions. A Mokken scale analysis was conducted to compare the homogeneity of HAM-D17 with that of HAM-D6. Results: At week 8, the guided-care arm demonstrated statistically significant benefit over TAU when the HAM-D6 (Δ = 4.4%, p = 0.023) was used as the continuous measure of symptom improvement, but not when using the HAM-D17 (Δ = 3.2%, p = 0.069). Response rates increased significantly for guided-care compared with TAU when evaluated using both HAM-D6 (Δ = 7.0%, p = 0.004) and HAM-D17 (Δ = 6.3%, p = 0.007). Remission rates also were significantly greater for guided-care versus TAU using both measures (HAM-D6 Δ = 4.6%, p = 0.031; HAM-D17 Δ = 5.5%, p = 0.005). Patients in the guided-care arm who at baseline were taking medications predicted to have gene-drug interactions showed further increased benefit over TAU at week 8 for symptom improvement (Δ = 7.3%, p = 0.004) response (Δ = 10.0%, p = 0.001) and remission (Δ = 7.9%, p = 0.005) using HAM-D6. All outcomes showed continued improvement through week 24. Mokken scale analysis demonstrated the homogeneity and unidimensionality of HAM-D6, but not of HAM-D17, across treatment arms. Conclusions: The HAM-D6 scale identified a statistically significant difference in symptom improvement between combinatorial pharmacogenomics-guided care and TAU, whereas the HAM-D17 did not. The demonstrated utility of pharmacogenomics-guided treatment over TAU as detected by the HAM-D6 highlights its value for future biomarker-guided trials comparing active treatment arms. © 2019 The Author(s).

Author Keywords
Antidepressant;  Assessment;  Biomarker;  Clinical trial;  Clinical utility;  Comparative effectiveness;  Decision-making;  Depression;  Genetics;  Pharmacogenomics

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

A Targeted Gene Panel That Covers Coding, Non-coding and Short Tandem Repeat Regions Improves the Diagnosis of Patients With Neurodegenerative Diseases
(2019) Frontiers in Neuroscience, 13, art. no. 1324, . 

Yu, A.C.-S.^{a b} , Yim, A.K.-Y.^{a c} , Chan, A.Y.-Y.^d , Yuen, L.Y.P.^e , Au, W.C.^{d f} , Cheng, T.H.T.^e , Lin, X.^b , Li, J.-W.^a , Chan, L.W.L.^g , Mok, V.C.T.^{d f} , Chan, T.-F.^{a b f} , Chan, H.Y.E.^{a b f}

^a Codex Genetics Limited, Shatin, Hong Kong
^b School of Life Sciences, The Chinese University of Hong Kong, Shatin, China
^c Computational and System Biology Program, Washington University School of Medicine, Saint Louis, MO, United States
^d Division of Neurology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, China
^e Department of Chemical Pathology, The Chinese University of Hong Kong, Shatin, China
^f Gerald Choa Neuroscience Centre, The Chinese University of Hong Kong, Shatin, China
^g Alice Ho Miu Ling Nethersole Hospital, Tai Po, Hong Kong

Abstract
Genetic testing for neurodegenerative diseases (NDs) is highly challenging because of genetic heterogeneity and overlapping manifestations. Targeted-gene panels (TGPs), coupled with next-generation sequencing (NGS), can facilitate the profiling of a large repertoire of ND-related genes. Due to the technical limitations inherent in NGS and TGPs, short tandem repeat (STR) variations are often ignored. However, STR expansions are known to cause such NDs as Huntington’s disease and spinocerebellar ataxias type 3 (SCA3). Here, we studied the clinical utility of a custom-made TGP that targets 199 NDs and 311 ND-associated genes on 118 undiagnosed patients. At least one known or likely pathogenic variation was found in 54 patients; 27 patients demonstrated clinical profiles that matched the variants; and 16 patients whose original diagnosis were refined. A high concordance of variant calling were observed when comparing the results from TGP and whole-exome sequencing of four patients. Our in-house STR detection algorithm has reached a specificity of 0.88 and a sensitivity of 0.82 in our SCA3 cohort. This study also uncovered a trove of novel and recurrent variants that may enrich the repertoire of ND-related genetic markers. We propose that a combined comprehensive TGPs-bioinformatics pipeline can improve the clinical diagnosis of NDs. © Copyright © 2019 Yu, Yim, Chan, Yuen, Au, Cheng, Lin, Li, Chan, Mok, Chan and Chan.

Author Keywords
clinical decision support;  gene panel;  high-throughput sequencing;  neurodegenerative diseases;  short tandem repeat;  undiagnosed diseases

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

The local translation of KNa in dendritic projections of auditory neurons and the roles of KNa in the transition from hidden to overt hearing loss
(2019) Aging, 11 (23), pp. 11541-11564. 

Lee, J.H.^a , Kang, M.^a , Park, S.^a , Perez-Flores, M.C.^a , Zhang, X.-D.^b , Wang, W.^a , Gratton, M.A.^c , Chiamvimonvat, N.^b , Yamoah, E.N.^a

^a Department of Physiology and Cell Biology, School of Medicine, University of Nevada Reno, Reno, United States
^b Department of Internal Medicine, Division of Cardiology, University of California Davis, Davis, CA 95616, USA
^c Department of Otolaryngology, Head and Neck Surgery, Washington University St. Louis, St. Louis, MO 63110, USA

Abstract
Local and privileged expression of dendritic proteins allows segregation of distinct functions in a single neuron but may represent one of the underlying mechanisms for early and insidious presentation of sensory neuropathy. Tangible characteristics of early hearing loss (HL) are defined in correlation with nascent hidden hearing loss (HHL) in humans and animal models. Despite the plethora of causes of HL, only two prevailing mechanisms for HHL have been identified, and in both cases, common structural deficits are implicated in inner hair cell synapses, and demyelination of the auditory nerve (AN). We uncovered that Na+-activated K+ (KNa) mRNA and channel proteins are distinctly and locally expressed in dendritic projections of primary ANs and genetic deletion of KNa channels (Kcnt1 and Kcnt2) results in the loss of proper AN synaptic function, characterized as HHL, without structural synaptic alterations. We further demonstrate that the local functional synaptic alterations transition from HHL to increased hearing-threshold, which entails changes in global Ca2+ homeostasis, activation of caspases 3/9, impaired regulation of inositol triphosphate receptor 1 (IP3R1), and apoptosis-mediated neurodegeneration. Thus, the present study demonstrates how local synaptic dysfunction results in an apparent latent pathological phenotype (HHL) and, if undetected, can lead to overt HL. It also highlights, for the first time, that HHL can precede structural synaptic dysfunction and AN demyelination. The stepwise cellular mechanisms from HHL to canonical HL are revealed, providing a platform for intervention to prevent lasting and irreversible age-related hearing loss (ARHL).

Author Keywords
age-related hearing loss;  auditory neurons;  axonal protein translation;  hearing loss;  potassium channels

Document Type: Article
Publication Stage: Final
Source: Scopus

Maternal Fluoxetine Exposure Alters Cortical Hemodynamic and Calcium Response of Offspring to Somatosensory Stimuli
(2019) eNeuro, 6 (6), . 

Rahn, R.M.^{a b c} , Maloney, S.E.^{c d} , Brier, L.M.^a , Dougherty, J.D.^{b c d} , Culver, J.P.^{a e f}

^a Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110
^b Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110
^c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110
^d Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO 63110
^e Department of Biomedical Engineering, Washington University, St. Louis, MO 63110
^f Department of Physics, Washington University, St. Louis, MO 63110

Abstract
Epidemiological studies have found an increased incidence of neurodevelopmental disorders in populations prenatally exposed to selective serotonin reuptake inhibitors (SSRIs). Optical imaging provides a minimally invasive way to determine if perinatal SSRI exposure has long-term effects on cortical function. Herein we probed the functional neuroimaging effects of perinatal SSRI exposure in a fluoxetine (FLX)-exposed mouse model. While resting-state homotopic contralateral functional connectivity was unperturbed, the evoked cortical response to forepaw stimulation was altered in FLX mice. The stimulated cortex showed decreased activity for FLX versus controls, by both hemodynamic responses [oxyhemoglobin (HbO2)] and neuronal calcium responses (Thy1-GCaMP6f fluorescence). Significant alterations in both cortical HbO2 and calcium response amplitude were seen in the cortex ipsilateral to the stimulated paw in FLX as compared to controls. The cortical regions of largest difference in activation between FLX and controls also were consistent between HbO2 and calcium contrasts at the end of stimulation. Taken together, these results suggest a global loss of response signal amplitude in FLX versus controls. These findings indicate that perinatal SSRI exposure has long-term consequences on somatosensory cortical responses. Copyright © 2019 Rahn et al.

Author Keywords
calcium imaging;  cerebral hemodynamics;  fluoxetine;  serotonin;  somatosensory

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

The Effect of Psychological Impairment on Outcomes in Patients With Prearthritic Hip Disorders: A Systematic Review and Meta-analysis
(2019) American Journal of Sports Medicine, . 

Cheng, A.L.^a , Schwabe, M.^b , Doering, M.M.^c , Colditz, G.A.^d , Prather, H.^a

^a Division of Physical Medicine and Rehabilitation, Department of Orthopaedic Surgery, Washington University School of Medicine, St Louis, MO, United States
^b Washington University School of Medicine, St Louis, MO, United States
^c Bernard Becker Medical Library, Washington University School of Medicine, St Louis, MO, United States
^d Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, MO, United States

Abstract
Background: Recent studies have suggested that mental health disorders negatively affect postoperative outcomes in patients with femoroacetabular impingement (FAI). However, the outcome measures reported and the effect sizes have varied. Furthermore, it is unknown whether similar effects are present in young adults with other hip disorders such as acetabular dysplasia. Purpose: To synthesize current evidence regarding the effect of baseline psychological impairment on postintervention outcomes in patients with prearthritic hip disorders. Study Design: Systematic review and meta-analysis. Methods: In February 2019, the Ovid Medline, Embase, Scopus, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and ClinicalTrials.gov databases were searched for longitudinal studies that evaluated the effect of baseline psychological impairment (such as depression or anxiety) on a postintervention clinical outcome in patients with prearthritic hip disorders including FAI, acetabular dysplasia, and/or acetabular labral tears. Descriptive measures of study quality and bias were recorded, and studies that reported statistically comparable outcomes were analyzed in meta-analyses through use of random effects models. Results: We identified 12 eligible studies, all of which specifically evaluated patients with FAI after hip arthroscopy. No eligible studies described patients with acetabular dysplasia. Of the included studies, 8 studies reported odds ratios (ORs). The other 4 studies reported mean postoperative scores on patient-reported outcome measures (PROMs), all of which were scored from 0 to 100, with higher numbers being favorable. Patients with psychological impairment were less likely to achieve a favorable outcome after arthroscopy (OR, 0.74; 95% CI, 0.62 to 0.88; P <.001), and they reported worse postoperative PROM scores compared with nonimpaired patients (weighted mean difference, −20.2 points; 95% CI, −32.9 to −7.5; P <.001). Conclusion: Baseline psychological impairment is associated with clinically significantly worse outcomes in patients with femoroacetabular impingement who undergo hip arthroscopy. More standardized reporting would facilitate improved understanding of this important, potentially modifiable risk factor. Registration: CRD42019124836 (PROSPERO). © 2019 The Author(s).

Author Keywords
acetabular dysplasia;  anxiety;  depression;  femoroacetabular impingement;  mental health;  prearthritic hip disorder;  psychological impairment

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Testing for N-methyl-d-aspartate Receptor Autoantibodies in Clinical Practice
(2019) Canadian Journal of Neurological Sciences, pp. 69-76. 

Brooks, J.^a , Yarbrough, M.L.^b , Bucelli, R.C.^c , Day, G.S.^c

^a Department of Medicine, Division of Neurology, University of Ottawa, Ottawa, ON, Canada
^b Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, United States
^c Knight Alzheimer Disease Research Center, Department of Neurology, Washington University School of Medicine, 4488 Forest Park Ave, St. Louis, MO 63108, United States

Abstract
Background:The diagnosis of anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis relies on the detection of NMDAR IgG autoantibodies in the serum or cerebrospinal fluid (CSF) of symptomatic patients. Commercial kits are available that allow NMDAR IgG autoantibodies to be measured in local laboratories. However, the performance of these tests outside of reference laboratories is unknown.Objectives:To report an unexpectedly low rate of NMDAR autoantibody detection in serum from patients with anti-NMDAR encephalitis tested using a commercially available diagnostic kit in an exemplar clinical laboratory.Methods:Paired CSF and serum samples from seven patients with definite anti-NMDAR encephalitis were tested for NMDAR IgG autoantibodies using commercially available cell-based assays run according to manufacturer’s recommendations. Rates of autoantibody detection in serum tested at our center were compared with those derived from systematic review and meta-analyses incorporating studies published during or before March 2019.Results:NMDAR IgG autoantibodies were detected in the CSF of all patients tested at our clinical laboratory but not in paired serum samples. Rates of the detection were lower than those previously reported. A similar association was recognized through meta-analyses, with lower odds of NMDAR IgG autoantibody detection associated with serum testing performed in nonreference laboratories.Conclusions:Commercial kits may yield lower-than-expected rates of NMDAR IgG autoantibody detection in serum when run in exemplar clinical (nonreference) laboratories. Additional studies are needed to decipher the factors that contribute to lower-than-expected rates of serum positivity. CSF testing is recommended in patients with suspected anti-NMDAR encephalitis. © 2019 The Canadian Journal of Neurological Sciences Inc.

Author Keywords
Anti-NMDA receptor encephalitis;  Autoimmune encephalitis;  Diagnostic testing

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

High-Throughput Analysis of Retinal Cis-Regulatory Networks by Massively Parallel Reporter Assays
(2019) Advances in Experimental Medicine and Biology, 1185, pp. 359-364. 

Oh, I.Y.^a , Chen, S.^{a b}

^a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, MO, United States
^b Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
Inherited retinal degenerations are diverse and debilitating blinding diseases. Genetic tests and exome sequencing have identified mutations in many protein-coding genes associated with such diseases, but causal sequence variants remain to be found in many retinopathy cases. Since 99% of our genome does not code for protein but contains cis-regulatory elements (CREs) that regulate the expression of essential genes, CRE variants might hold the answer for some of these cases. However, identifying functional CREs within the noncoding genome and predicting the pathogenicity of CRE variants pose a significant challenge. Here, we review the development of massively parallel reporter assays in the mouse retina, its use in dissecting retinal cis-regulatory networks, and its potential application for developing therapies. © 2019, Springer Nature Switzerland AG.

Author Keywords
Cis-regulatory element;  CRE-seq;  CRX;  High-throughput functional analysis;  Massively parallel reporter assay (MPRA);  Noncoding DNA;  NRL;  Retina transcription factor;  Transcriptional regulation

Document Type: Book Chapter
Publication Stage: Final
Source: Scopus

Including culture in programs to reduce stigma toward people with mental disorders in low- and middle-income countries
(2019) Transcultural Psychiatry, . 

Mascayano, F.^a , Toso-Salman, J.^a , Ho, Y.C.S.^a , Dev, S.^a , Tapia, T.^a , Thornicroft, G.^b , Cabassa, L.J.^c , Khenti, A.^d , Sapag, J.^{d e f} , Bobbili, S.J.^d , Alvarado, R.^g , Yang, L.H.^{a h} , Susser, E.^{a h}

^a Columbia University, United States
^b King’s College London, United Kingdom
^c Washington University in St. Louis, United States
^d IMHPR, Centre for Addiction and Mental Health, Canada
^e Mental Health, Catholic University of Chile, Chile
^f Dalla Lana School of Public Health, University of Toronto, Canada
^g Universidad de Chile, Chile
^h New York University College of Global Public Health, United States

Abstract
Stigma is one of the main barriers for the full implementation of mental health services in low- and middle-income countries (LMICs). Recently, many initiatives to reduce stigma have been launched in these settings. Nevertheless, the extent to which these interventions are effective and culturally sensitive remains largely unknown. The present review addresses these two issues by conducting a comprehensive evaluation of interventions to reduce stigma toward mental illness that have been implemented in LMICs. We conducted a scoping review of scientific papers in the following databases: PubMed, Google Scholar, EBSCO, OVID, Embase, and SciELO. Keywords in English, Spanish, and Portuguese were included. Articles published from January 1990 to December 2017 were incorporated into this article. Overall, the studies were of low-to-medium methodological quality—most only included evaluations after intervention or short follow-up periods (1–3 months). The majority of programs focused on improving knowledge and attitudes through the education of healthcare professionals, community members, or consumers. Only 20% (5/25) of the interventions considered cultural values, meanings, and practices. This gap is discussed in the light of evidence from cultural studies conducted in both low and high income countries. Considering the methodological shortcomings and the absence of cultural adaptation, future efforts should consider better research designs, with longer follow-up periods, and more suitable strategies to incorporate relevant cultural features of each community. © The Author(s) 2019.

Author Keywords
interventions;  low- and middle-income countries;  mental illness;  stigma

Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Access Type: Open Access