WashU weekly Neuroscience publications

Hypothalamic orexin and mechanistic target of rapamycin activation mediate sleep dysfunction in a mouse model of tuberous sclerosis complex
(2020) Neurobiology of Disease, 134, art. no. 104615, . 

Zhang, B.^a , Guo, D.^a , Han, L.^a , Rensing, N.^a , Satoh, A.^b , Wong, M.^a

^a Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Sleep and Aging Regulation Research Project Team, National Center for Geriatrics and Gerontology, Aichi, 474-8511, Japan

Abstract
Tuberous sclerosis complex (TSC) is a genetic disease related to hyperactivation of the mechanistic target of rapamycin (mTOR) pathway and manifested by neurological symptoms, such as epilepsy and sleep disorders. The pathophysiology of sleep dysfunction is poorly understood and is likely multifactorial, but may involve intrinsic biological regulators in the brain. Here, we characterized a mouse model of sleep disorders in TSC and investigated mechanisms of sleep dysfunction in this conditional knockout model involving inactivation of the Tsc1 gene in neurons and astrocytes (Tsc1GFAPCKO mice). Sleep studies utilizing EEG, EMG, and behavioral analysis found that Tsc1GFAPCKO mice have decreased REM sleep and impaired sleep-wake differentiation between light and dark phases. mTOR activity and orexin expression were increased in hypothalamic sections and cultured hypothalamic neurons from Tsc1GFAPCKO mice. Both the sleep abnormalities and increased orexin expression in Tsc1GFAPCKO mice were reversed by rapamycin treatment, indicating their dependence on mTOR activation. An orexin antagonist, suvorexant, also restored normal REM levels in Tsc1GFAPCKO mice. These results identify a novel mechanistic link between mTOR and orexin in the hypothalamus related to sleep dysfunction and suggest a targeted therapeutic approach to sleep disorders in TSC. © 2019 Elsevier Inc.

Author Keywords
Mice;  Orexin;  Rapamycin;  Seizure;  Sleep;  Tuberous sclerosis

Document Type: Article
Publication Stage: Final
Source: Scopus

Delineating and validating higher-order dimensions of psychopathology in the Adolescent Brain Cognitive Development (ABCD) study
(2019) Translational Psychiatry, 9 (1), art. no. 261, . 

Michelini, G.^a , Barch, D.M.^b , Tian, Y.^c , Watson, D.^d , Klein, D.N.^e , Kotov, R.^a

^a Department of Psychiatry & Behavioral Health, Stony Brook University, Stony Brook, NY, United States
^b Departments of Psychological & Brain Sciences, Psychiatry and Radiology, Washington University, St. Louis, MO, United States
^c Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, United States
^d Department of Psychology, University of Notre Dame, Notre Dame, IN, United States
^e Department of Psychology, Stony Brook University, Stony Brook, NY, United States

Abstract
Hierarchical dimensional systems of psychopathology promise more informative descriptions for understanding risk and predicting outcome than traditional diagnostic systems, but it is unclear how many major dimensions they should include. We delineated the hierarchy of childhood and adult psychopathology and validated it against clinically relevant measures. Participants were 9987 9- and 10-year-old children and their parents from the Adolescent Brain Cognitive Development (ABCD) study. Factor analyses of items from the Child Behavior Checklist and Adult Self-Report were run to delineate hierarchies of dimensions. We examined the familial aggregation of the psychopathology dimensions, and the ability of different factor solutions to account for risk factors, real-world functioning, cognitive functioning, and physical and mental health service utilization. A hierarchical structure with a general psychopathology (‘p’) factor at the apex and five specific factors (internalizing, somatoform, detachment, neurodevelopmental, and externalizing) emerged in children. Five similar dimensions emerged also in the parents. Child and parent p-factors correlated highly (r = 0.61, p < 0.001), and smaller but significant correlations emerged for convergent dimensions between parents and children after controlling for p-factors (r = 0.09−0.21, p < 0.001). A model with child p-factor alone explained mental health service utilization (R2 = 0.23, p < 0.001), but up to five dimensions provided incremental validity to account for developmental risk and current functioning in children (R2 = 0.03−0.19, p < 0.001). In this first investigation comprehensively mapping the psychopathology hierarchy in children and adults, we delineated a hierarchy of higher-order dimensions associated with a range of clinically relevant validators. These findings hold important implications for psychiatric nosology and future research in this sample. © 2019, The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus

Prospective natural history study of C9orf72 ALS clinical characteristics and biomarkers
(2019) Neurology, 93 (17), pp. e1605-e1617. 

Cammack, A.J., Atassi, N., Hyman, T., van den Berg, L.H., Harms, M., Baloh, R.H., Brown, R.H., van Es, M.A., Veldink, J.H., de Vries, B.S., Rothstein, J.D., Drain, C., Jockel-Balsarotti, J., Malcolm, A., Boodram, S., Salter, A., Wightman, N., Yu, H., Sherman, A.V., Esparza, T.J., McKenna-Yasek, D., Owegi, M.A., Douthwright, C., McCampbell, A., Ferguson, T., Cruchaga, C., Cudkowicz, M., Miller, T.M., Alzheimer’s Disease Neuroimaging Initiative

From the Department of Neurology (A.J.C., T.H., C.D., J.J.-B., A.M., S.B., A.S., T.J.E., C.C., T.M.M.), Washington University School of Medicine, St. Louis, MO; Department of Neurology (N.A., H.Y., A.V.S., M.C.), Neurological Clinical Research Institute, Massachusetts General Hospital, Boston; Department of Neurology (L.H.v.d.B., M.A.v.E., J.H.V., B.S.d.V.), Brain Center Rudolf Magnus, University Medical Center Utrecht, University Utrecht, the Netherlands; Department of Neurology (M.H.), Columbia University, New York, NY; Department of Neurology (R.H. Baloh), Cedars-Sinai Medical Center, Los Angeles, CA; Department of Neurology (R.H. Brown, N.W., D.M.-Y., M.A.O., C.D.), University of Massachusetts, Worcester; Department of Neurology (J.D.R.), Johns Hopkins University, Baltimore, MD; and Biogen Inc. (A.M., T.F.), Boston, MA

Abstract
OBJECTIVE: To define the natural history of the C9orf72 amyotrophic lateral sclerosis (C9ALS) patient population, develop disease biomarkers, and characterize patient pathologies. METHODS: We prospectively collected clinical and demographic data from 116 symptomatic C9ALS and 12 non-amyotrophic lateral sclerosis (ALS) full expansion carriers across 7 institutions in the United States and the Netherlands. In addition, we collected blood samples for DNA repeat size assessment, CSF samples for biomarker identification, and autopsy samples for dipeptide repeat protein (DPR) size determination. Finally, we collected retrospective clinical data via chart review from 208 individuals with C9ALS and 450 individuals with singleton ALS. RESULTS: The mean age at onset in the symptomatic prospective cohort was 57.9 ± 8.3 years, and median duration of survival after onset was 36.9 months. The monthly change was -1.8 ± 1.7 for ALS Functional Rating Scale-Revised and -1.4% ± 3.24% of predicted for slow vital capacity. In blood DNA, we found that G4C2 repeat size correlates positively with age. In CSF, we observed that concentrations of poly(GP) negatively correlate with DNA expansion size but do not correlate with measures of disease progression. Finally, we found that size of poly(GP) dipeptides in the brain can reach large sizes similar to that of their DNA repeat derivatives. CONCLUSIONS: We present a thorough investigation of C9ALS natural history, providing the basis for C9ALS clinical trial design. We found that clinical features of this genetic subset are less variant than in singleton ALS. In addition, we identified important correlations of C9ALS patient pathologies with clinical and demographic data. © 2019 American Academy of Neurology.

Document Type: Article
Publication Stage: Final
Source: Scopus

Psychosocial moderation of polygenic risk for cannabis involvement: the role of trauma exposure and frequency of religious service attendance
(2019) Translational Psychiatry, 9 (1), p. 269. 

Meyers, J.L.^a , Salvatore, J.E.^b , Aliev, F.^b , Johnson, E.C.^c , McCutcheon, V.V.^c , Su, J.^b , Kuo, S.I.-C.^b , Lai, D.^d , Wetherill, L.^d , Wang, J.C.^e , Chan, G.^f , Hesselbrock, V.^f , Foroud, T.^d , Bucholz, K.K.^c , Edenberg, H.J.^d , Dick, D.M.^b , Porjesz, B.^a , Agrawal, A.^c

^a Henri Begleiter Neurodynamics Laboratory, Department of Psychiatry, State University of New York Downstate Medical Center, Brooklyn, NY, 11203, USA
^b Virginia Commonwealth University, VA, Richmond, United States
^c Washington University School of Medicine, St. Louis, MO, 63110, USA
^d Indiana University School of Medicine, IN, Indianapolis, 46202, United States
^e Mount Sinai School of Medicine, NY, NY 10029, United States
^f University of Connecticut School of Medicine, CTCT, United States

Abstract
Cannabis use and disorders (CUD) are influenced by multiple genetic variants of small effect and by the psychosocial environment. However, this information has not been effectively incorporated into studies of gene-environment interaction (GxE). Polygenic risk scores (PRS) that aggregate the effects of genetic variants can aid in identifying the links between genetic risk and psychosocial factors. Using data from the Pasman et al. GWAS of cannabis use (meta-analysis of data from the International Cannabis Consortium and UK Biobank), we constructed PRS in the Collaborative Study on the Genetics of Alcoholism (COGA) participants of European (N: 7591) and African (N: 3359) ancestry. The primary analyses included only individuals of European ancestry, reflecting the ancestral composition of the discovery GWAS from which the PRS was derived. Secondary analyses included the African ancestry sample. Associations of PRS with cannabis use and DSM-5 CUD symptom count (CUDsx) and interactions with trauma exposure and frequency of religious service attendance were examined. Models were adjusted for sex, birth cohort, genotype array, and ancestry. Robustness models were adjusted for cross-term interactions. Higher PRS were associated with a greater likelihood of cannabis use and with CUDsx among participants of European ancestry (p < 0.05 and p < 0.1 thresholds, respectively). PRS only influenced cannabis use among those exposed to trauma (R2: 0.011 among the trauma exposed vs. R2: 0.002 in unexposed). PRS less consistently influenced cannabis use among those who attend religious services less frequently; PRS × religious service attendance effects were attenuated when cross-term interactions with ancestry and sex were included in the model. Polygenic liability to cannabis use was related to cannabis use and, less robustly, progression to symptoms of CUD. This study provides the first evidence of PRS × trauma for cannabis use and demonstrates that ignoring important aspects of the psychosocial environment may mask genetic influences on polygenic traits.

Document Type: Article
Publication Stage: Final
Source: Scopus

Cis-regulatory basis of sister cell type divergence in the vertebrate retina
(2019) eLife, 8, . 

Murphy, D.P., Hughes, A.E., Lawrence, K.A., Myers, C.A., Corbo, J.C.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States

Abstract
Multicellular organisms evolved via repeated functional divergence of transcriptionally related sister cell types, but the mechanisms underlying sister cell type divergence are not well understood. Here, we study a canonical pair of sister cell types, retinal photoreceptors and bipolar cells, to identify the key cis-regulatory features that distinguish them. By comparing open chromatin maps and transcriptomic profiles, we found that while photoreceptor and bipolar cells have divergent transcriptomes, they share remarkably similar cis-regulatory grammars, marked by enrichment of K50 homeodomain binding sites. However, cell class-specific enhancers are distinguished by enrichment of E-box motifs in bipolar cells, and Q50 homeodomain motifs in photoreceptors. We show that converting K50 motifs to Q50 motifs represses reporter expression in bipolar cells, while photoreceptor expression is maintained. These findings suggest that partitioning of Q50 motifs within cell type-specific cis-regulatory elements was a critical step in the evolutionary divergence of the bipolar transcriptome from that of photoreceptors. © 2019, Murphy et al.

Author Keywords
ATAC-seq;  bipolar cell;  chromosomes;  cis-regulatory element;  gene expression;  genetics;  genomics;  mouse;  photoreceptor;  retina;  sister cell type

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

Lack of hepatic apoE does not influence early Aβ deposition: observations from a new APOE knock-in model
(2019) Molecular Neurodegeneration, 14 (1), p. 37. 

Huynh, T.-P.V.^{a b} , Wang, C.^a , Tran, A.C.^a , Tabor, G.T.^{a b} , Mahan, T.E.^a , Francis, C.M.^a , Finn, M.B.^a , Spellman, R.^a , Manis, M.^a , Tanzi, R.E.^c , Ulrich, J.D.^a , Holtzman, D.M.^a

^a Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
^b Medical Scientist Training Program (MSTP), Washington University School of Medicine, St. Louis, MO, USA
^c McCance Center for Brain Health and Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, MA, Charlestown, United States

Abstract
BACKGROUND: The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer disease (AD). ApoE is produced by both astrocytes and microglia in the brain, whereas hepatocytes produce the majority of apoE found in the periphery. Studies using APOE knock-in and transgenic mice have demonstrated a strong isoform-dependent effect of apoE on the accumulation of amyloid-β (Aβ) deposition in the brain in the form of both Aβ-containing amyloid plaques and cerebral amyloid angiopathy. However, the specific contributions of different apoE pools to AD pathogenesis remain unknown. METHODS: We have begun to address these questions by generating new lines of APOE knock-in (APOE-KI) mice (ε2/ε2, ε3/ε3, and ε4/ε4) where the exons in the coding region of APOE are flanked by loxP sites, allowing for cell type-specific manipulation of gene expression. We assessed these mice both alone and after crossing them with mice with amyloid deposition in the brain. Using biochemical and histological methods. We also investigated how removal of APOE expression from hepatocytes affected cerebral amyloid deposition. RESULTS: As in other APOE knock-in mice, apoE protein was present predominantly in astrocytes in the brain under basal conditions and was also detected in reactive microglia surrounding amyloid plaques. Primary cultured astrocytes and microglia from the APOE-KI mice secreted apoE in lipoprotein particles of distinct size distribution upon native gel analysis with microglial particles being substantially smaller than the HDL-like particles secreted by astrocytes. Crossing of APP/PS1 transgenic mice to the different APOE-KI mice recapitulated the previously described isoform-specific effect (ε4 > ε3) on amyloid plaque and Aβ accumulation. Deletion of APOE in hepatocytes did not alter brain apoE levels but did lead to a marked decrease in plasma apoE levels and changes in plasma lipid profile. Despite these changes in peripheral apoE and on plasma lipids, cerebral accumulation of amyloid plaques in APP/PS1 mice was not affected. CONCLUSIONS: Altogether, these new knock-in strains offer a novel and dynamic tool to study the role of APOE in AD pathogenesis in a spatially and temporally controlled manner.

Author Keywords
Albumin;  Amyloid;  apoE;  apoE particle;  Apolipoprotein E;  Aβ;  Cre-loxP;  Mouse model

Document Type: Article
Publication Stage: Final
Source: Scopus

Redefining Noradrenergic Neuromodulation of Behavior: Impacts of a Modular Locus Coeruleus Architecture
(2019) The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 39 (42), pp. 8239-8249. 

Chandler, D.J.^a , Jensen, P.^b , McCall, J.G.^c , Pickering, A.E.^{d e} , Schwarz, L.A.^f , Totah, N.K.^{g h i}

^a Department of Cell Biology and Neuroscience, Rowan University School of Osteopathic Medicine, Stratford, NJ 08084, United States
^b Neurobiology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle ParkNC 27709
^c Department of Anesthesiology, Department of Pharmaceutical and Administrative Sciences, St. Louis College of Pharmacy, Center for Clinical Pharmacology, St. Louis College of Pharmacy and Washington University School of Medicine, Washington University Pain Center, Washington University in St. Louis, St. Louis, MO 63110, United States
^d School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, United Kingdom
^e Pain and Critical Care Sciences, Translational Health Sciences, Bristol Medical School, Bristol Royal Infirmary, Bristol, BS2 8HW, United Kingdom
^f St. Jude Children’s Research Hospital, Memphis, TN 38105, United States
^g Department of Physiology of Cognitive Processes, Max Planck Institute for Biological Cybernetics, Tübingen72076, Germany
^h Helsinki Institute of Life Science, Helsinki, 00014, Finland
ⁱ School of Pharmacy, University of Helsinki, Helsinki, 00014, Finland

Abstract
The locus coeruleus (LC) is a seemingly singular and compact neuromodulatory nucleus that is a prominent component of disparate theories of brain function due to its broad noradrenergic projections throughout the CNS. As a diffuse neuromodulatory system, noradrenaline affects learning and decision making, control of sleep and wakefulness, sensory salience including pain, and the physiology of correlated forebrain activity (ensembles and networks) and brain hemodynamic responses. However, our understanding of the LC is undergoing a dramatic shift due to the application of state-of-the-art methods that reveal a nucleus of many modules that provide targeted neuromodulation. Here, we review the evidence supporting a modular LC based on multiple levels of observation (developmental, genetic, molecular, anatomical, and neurophysiological). We suggest that the concept of the LC as a singular nucleus and, alongside it, the role of the LC in diverse theories of brain function must be reconsidered. Copyright © 2019 the authors.

Author Keywords
anxiety;  development;  executive function;  locus coeruleus;  pain;  stress

Document Type: Article
Publication Stage: Final
Source: Scopus

Association of Acquired and Heritable Factors With Intergenerational Differences in Age at Symptomatic Onset of Alzheimer Disease Between Offspring and Parents With Dementia
(2019) JAMA Network Open, 2 (10), p. e1913491. 

Day, G.S.^{a b} , Cruchaga, C.^{a c} , Wingo, T.^{d e} , Schindler, S.E.^{a b} , Coble, D.^{a f} , Morris, J.C.^{a b}

^a Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine in St Louis, St Louis, MO, United States
^b Department of Neurology, Washington University School of Medicine in St Louis, St Louis, MO, United States
^c Department of Psychiatry, Washington University School of Medicine in St Louis, St Louis, MO, United States
^d Department of Neurology, Emory University, Atlanta, Georgia
^e Department of Human Genetics, Emory University, Atlanta, Georgia
^f Department of Biostatistics, Washington University School of Medicine in St Louis, St Louis, MO, United States

Abstract
Importance: Acquired and heritable traits are associated with dementia risk; however, how these traits are associated with age at symptomatic onset (AAO) of Alzheimer disease (AD) is unknown. Identifying the associations of acquired and heritable factors with variability in intergenerational AAO of AD could facilitate diagnosis, assessment, and counseling of the offspring of parents with AD. Objective: To quantify the associations of acquired and heritable factors with intergenerational differences in AAO of AD. Design, Setting, and Participants: This nested cohort study used data from the Knight Alzheimer Disease Research Center that included community-dwelling participants with symptomatic AD, parental history of dementia, and available DNA data who were enrolled in prospective studies of memory and aging from September 1, 2005, to August 31, 2016. Clinical, biomarker, and genetic data were extracted on January 17, 2017, and data analyses were conducted from July 1, 2017, to August 20, 2019. Main Outcomes and Measures: The associations of acquired (ie, years of education; body mass index; history of cardiovascular disease, hypertension, hypercholesterolemia, diabetes, active depression within 2 years, traumatic brain injury, tobacco use, and unhealthy alcohol use; and retrospective determination of AAO) and heritable factors (ie, ethnicity/race, paternal or maternal inheritance, parental history of early-onset dementia, APOE ε4 allele status, and AD polygenic risk scores) to intergenerational difference in AAO of AD were quantified using stepwise forward multivariable regression. Missense or frameshift variants within genes associated with AD pathogenesis were screened using whole-exome sequencing. Results: There were 164 participants with symptomatic AD, known parental history of dementia, and available DNA data (mean [SD] age, 70.9 [8.3] years; 90 [54.9%] women) included in this study. Offspring were diagnosed with symptomatic AD a mean (SD) 6.1 (10.7) years earlier than their parents (P < .001). The adjusted R2 for measured acquired and heritable factors for intergenerational difference in AAO of AD was 0.29 (F8,155 = 9.13; P < .001). Paternal (β = -9.52 [95% CI, -13.79 to -5.25]) and maternal (β = -6.68 [95% CI, -11.61 to -1.75]) history of dementia, more years of education (β = -0.58 [95% CI -1.08 to -0.09]), and retrospective determination of AAO (β = -3.46 [95% CI, -6.40 to -0.52]) were associated with earlier-than-expected intergenerational difference in AAO of AD. Parental history of early-onset dementia (β = 21.30 [95% CI, 15.01 to 27.59]), presence of 1 APOE ε4 allele (β = 5.00 [95% CI, 2.11 to 7.88]), and history of hypertension (β = 3.81 [95% CI, 0.88 to 6.74]) were associated with later-than-expected intergenerational difference in AAO of AD. Missense or frameshift variants within genes associated with AD pathogenesis were more common in participants with the greatest unexplained variability in intergenerational AAO of AD (19 of 48 participants [39.6%] vs 26 of 116 participants [22.4%]; P = .03). Conclusions and Relevance: Acquired and heritable factors were associated with a substantial proportion of variability in intergenerational AAO of AD. Variants in genes associated with AD pathogenesis may contribute to unexplained variability, justifying further study.

Document Type: Article
Publication Stage: Final
Source: Scopus

Predicting Cognitive Improvement in Normal Pressure Hydrocephalus Patients Using Preoperative Neuropsychological Testing and Cerebrospinal Fluid Biomarkers
(2019) Clinical Neurosurgery, 85 (4), pp. E662-E669. Cited 1 time.

McGovern, R.A.^{a b} , Nelp, T.B.^b , Kelly, K.M.^b , Chan, A.K.^c , Mazzoni, P.^{d e} , Sheth, S.A.^f , Honig, L.S.^e , Teich, A.F.^g , McKhann, G.M.^b

^a Department of Neurosurgery, University of Minnesota, Minneapolis, MN, United States
^b Department of Neurological Surgery, Columbia University Medical Center, Neurological Institute, 710 W 168th St., New York, NY 10032, United States
^c Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United States
^d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Neurology, Columbia University Medical Center, New York, NY, United States
^f Department of Neurosurgery, Baylor College of Medicine, Houston, TX, United States
^g Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, United States

Abstract
BACKGROUND: Though it is well known that normal pressure hydrocephalus (NPH) patients can cognitively improve after ventriculoperitoneal shunting (VPS), one of the major dilemmas in NPH is the ability to prospectively predict which patients will improve. OBJECTIVE: To prospectively assess preoperative predictors of postshunt cognitive improvement. METHODS: This was a prospective observational cohort including 52 consecutive patients with approximately 1-yr follow-up. Patients underwent neuropsychological testing at baseline, postlumbar drainage, and postshunt. Cerebrospinal fluid (CSF) biomarkers and cortical biopsies were also collected to examine their relationship with postshunt cognitive improvement. RESULTS: Rey Auditory Verbal Learning Test-L (RAVLT-L) was the only neuropsychological test to demonstrate statistically significant improvement both postlumbar drain and postshunt. Improvement on the RAVLT-L postlumbar drain predicted improvement on the RAVLT-L postshunt. Patients with biopsies demonstrating Aβ+ Tau+ had lower ventricular CSF Aβ42 and higher lumbar CSF pTau compared to Aβ-Tau-patients. A receiver operating curve analysis using lumbar pTau predicted Aβ+ Tau+ biopsy status but was not related to neuropsychological test outcome. CONCLUSION: The RAVLT can be a useful preoperative predictor of postoperative cognitive improvement, and thus, we recommend using the RAVLT to evaluate NPH patients. CSF biomarkers could not be related to neuropsychological test outcome. Future research in a larger patient sample will help determine the prospective utility of CSF biomarkers in the evaluation of NPH patients. Copyright © 2019 by the Congress of Neurological Surgeons.

Author Keywords
Cognition;  CSF biomarkers;  Neuropsychology;  Normal pressure hydrocephalus;  Prospective cohort;  Rey Auditory Verbal Learning Test

Document Type: Article
Publication Stage: Final
Source: Scopus

Clinical variables and genetic risk factors associated with the acute outcome of ischemic stroke: A systematic review
(2019) Journal of Stroke, 21 (3), pp. 276-289. 

Torres-Aguila, N.P.^{a b} , Carrera, C.^{a b} , Muiño, E.^a , Cullell, N.^c , Cárcel-Márquez, J.^a , Gallego-Fabrega, C.^{a c} , González-Sánchez, J.^{a c d} , Bustamante, A.^b , Delgado, P.^b , Ibañez, L.^e , Heitsch, L.^{f g} , Krupinski, J.^{c d} , Montaner, J.^h , Martí-Fàbregas, J.ⁱ , Cruchaga, C.^e , Lee, J.-M.^g , Fernandez-Cadenas, I.^a , Acute Endophenotypes Group of the International Stroke Genetics Consortium (ISGC)^j

^a Stroke Pharmacogenomics and Genetics Laboratory, Sant Pau Research Institute, Barcelona, Spain
^b Neurovascular Research Laboratory, Vall d’Hebron Research Institute (VHIR), Autonomous University of Barcelona, Barcelona, Spain
^c Stroke Pharmacogenomics and Genetics Laboratory, Mutua Terrasa Foundation of Teaching and Research, Mutua Terrassa Hospital, Terrassa, Spain
^d Health Care Science Department, The Manchester Metropolitan University of All Saints, Manchester, United Kingdom
^e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^f Division of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, United States
^g Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^h Department of Neurology, Virgin Rocío and Macarena Hospitals, Institute of Biomedicine of Seville (IBiS), Seville, Spain
ⁱ Stroke Unit, Department of Neurology, Saint Cross and Saint Pau Hospital, Barcelona, Spain

Abstract
Stroke is a complex disease and one of the main causes of morbidity and mortality among the adult population. A huge variety of factors is known to influence patient outcome, including demographic variables, comorbidities or genetics. In this review, we expound what is known about the influence of clinical variables and related genetic risk factors on ischemic stroke outcome, focusing on acute and subacute outcome (within 24 to 48 hours after stroke and until day 10, respectively), as they are the first indicators of stroke damage. We searched the PubMed data base for articles that investigated the interaction between clinical variables or genetic factors and acute or subacute stroke outcome. A total of 61 studies were finally included in this review. Regarding the data collected, the variables consistently associated with acute stroke outcome are: glucose levels, blood pressure, presence of atrial fibrillation, prior statin treatment, stroke severity, type of acute treatment performed, severe neurological complications, leukocyte levels, and genetic risk factors. Further research and international efforts are required in this field, which should include genome-wide association studies. © 2019 Korean Stroke Society.

Author Keywords
Clinical variables;  Genetics;  Outcome;  Stroke

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

Predictors of success for combined endoscopic third ventriculostomy and choroid plexus cauterization in a North American setting: A Hydrocephalus Clinical Research Network study
(2019) Journal of Neurosurgery: Pediatrics, 24 (2), pp. 128-138. 

Riva-Cambrin, J.^a , Kestle, J.R.W.^b , Rozzelle, C.J.^c , Naftel, R.P.^d , Alvey, J.S.^b , Reeder, R.W.^b , Holubkov, R.^b , Browd, S.R.^e , Cochrane, D.D.^f , Limbrick, D.D., Jr.^g , Shannon, C.N.^d , Simon, T.D.^e , Tamber, M.S.^h , Wellons, J.C., III^d , Whitehead, W.E.ⁱ , Kulkarni, A.V.^g , Kestle, J.^j , Rozzelle, C.^k , Drake, J.^l , Kulkarni, A.^l , Whitehead, W.^m , Browd, S.ⁿ , Simon, T.ⁿ , Haupt-Man, J.ⁿ , Pollack, I.^o , Limbrick, D.^p , Wellons, J.^q , Naftel, R.^q , Shannon, C.^q , Tamber, M.^r , McDonald, P.^r , Riva-Cambrin, J.^s , Jackson, E.^t , Krieger, M.^u , Hankin-Son, T.^v , Pindrik, J.^w , Holubkov, R.^x , Hydrocephalus Clinical Research Network^y

^a Alberta Children’s Hospital, University of Calgary, Alberta, Canada
^b University of Utah, Salt Lake City, UT, United States
^c Children’s Hospital of Alabama, Birmingham, AL, United States
^d Vanderbilt University, Nashville, TN, United States
^e Seattle Children’s Hospital, Seattle, WA, United States
^f Hospital for Sick Children, University of Toronto, Ontario, Canada
^g St. Louis Children’s Hospital, St. Louis, MO, United States
^h Pittsburgh Children’s Hospital, Pittsburgh, PA, United States
ⁱ Texas Children’s Hospital, Houston, TX, United States
^j Primary Children’s Hospital, University of Utah, United States
^k Children’s Hospital of Alabama, University of Alabama at Birmingham, United States
^l Hospital for Sick Children, University of Toronto, Canada
^m Texas Children’s Hospital, Baylor College of Medicine, United States
ⁿ Seattle Children’s Hospital, University of Washington, United States
^o Children’s Hospital of Pittsburgh, University of Pittsburgh, United States
^p St. Louis Children’s Hospital, Washington University in St. Louis, United States
^q Monroe Carell Jr. Children’s Hospital at Vanderbilt, Vanderbilt University Medical Center, United States
^r British Columbia Children’s Hospital, University of British Columbia, Canada
^s Alberta Children’s Hospital, University of Calgary, Canada
^t Johns Hopkins Hospital, United States
^u Children’s Hospital of Los Angeles, United States
^v Children’s Hospital Colorado, United States
^w Nationwide Children’s Hospital, United States
^x HCRN DCC, Department of Pediatrics, University of Utah, United States

Abstract
OBJECTIVE Endoscopic third ventriculostomy combined with choroid plexus cauterization (ETV+CPC) has been adopted by many pediatric neurosurgeons as an alternative to placing shunts in infants with hydrocephalus. However, reported success rates have been highly variable, which may be secondary to patient selection, operative technique, and/or surgeon training. The objective of this prospective multicenter cohort study was to identify independent patient selection, operative technique, or surgical training predictors of ETV+CPC success in infants. METHODS This was a prospective cohort study nested within the Hydrocephalus Clinical Research Network’s (HCRN) Core Data Project (registry). All infants under the age of 2 years who underwent a first ETV+CPC between June 2006 and March 2015 from 8 HCRN centers were included. Each patient had a minimum of 6 months of follow-up unless censored by an ETV+CPC failure. Patient and operative risk factors of failure were examined, as well as formal ETV+CPC training, which was defined as traveling to and working with the experienced surgeons at CURE Children’s Hospital of Uganda. ETV+CPC failure was defined as the need for repeat ETV, shunting, or death. RESULTS The study contained 191 patients with a primary ETV+CPC conducted by 17 pediatric neurosurgeons within the HCRN. Infants under 6 months corrected age at the time of ETV+CPC represented 79% of the cohort. Myelomeningocele (26%), intraventricular hemorrhage associated with prematurity (24%), and aqueductal stenosis (17%) were the most common etiologies. A total of 115 (60%) of the ETV+CPCs were conducted by surgeons after formal training. Overall, ETV+CPC was successful in 48%, 46%, and 45% of infants at 6 months, 1 year, and 18 months, respectively. Young age (< 1 month) (adjusted hazard ratio [aHR] 1.9, 95% CI 1.0–3.6) and an etiology of post–intraventricular hemorrhage secondary to prematurity (aHR 2.0, 95% CI 1.1–3.6) were the only two independent predictors of ETV+CPC failure. Specific subgroups of ages within etiology categories were identified as having higher ETV+CPC success rates. Although training led to more frequent use of the flexible scope (p < 0.001) and higher rates of complete (> 90%) CPC (p < 0.001), training itself was not independently associated (aHR 1.1, 95% CI 0.7–1.8; p = 0.63) with ETV+CPC success. CONCLUSIONS This is the largest prospective multicenter North American study to date examining ETV+CPC. Formal ETV+CPC training was not found to be associated with improved procedure outcomes. Specific subgroups of ages within specific hydrocephalus etiologies were identified that may preferentially benefit from ETV+CPC. ©AANS 2019, except where prohibited by US copyright law

Author Keywords
Endoscopic third ventriculostomy combined with choroid plexus cauterization;  ETV+CPC;  HCRN;  Hydrocephalus;  Hydrocephalus Clinical Research Network;  Predictors

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

Patient-reported outcomes measurement information system physical function and pain interference in spine surgery
(2019) Journal of Neurosurgery: Spine, 31 (2), pp. 165-174. 

Khalifeh, J.M., Dibble, C.F., Hawasli, A.H., Ray, W.Z.

Department of Neurological Surgery, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
OBJECTIVE The Patient-Reported Outcomes Measurement Information System (PROMIS) is an adaptive, self-reported outcomes assessment tool that utilizes item response theory and computer adaptive testing to efficiently and precisely evaluate symptoms and perceived health status. Efforts to implement and report PROMIS outcomes in spine clinical practice remain limited. The objective of this retrospective cohort study is to evaluate the performance and psychometric properties of PROMIS physical function (PF) and pain interference (PI) among patients undergoing spine surgery. METHODS The authors identified all patients who underwent spine surgery at their institution between 2016 and 2018, and for whom there was retrievable PROMIS data. Descriptive statistics were calculated to summarize demographics, operative characteristics, and patient-reported outcomes. Assessments were evaluated preoperatively, and postoperatively within 2 months (early), 6 months (intermediate), and up to 2 years (late). Pairwise change scores were calculated to evaluate within-subjects differences and construct responsiveness over time. Pearson’s correlation coefficients were used to evaluate the association between PROMIS PF and PI domains. Subgroup analysis was performed based on the primary diagnoses of cervical radiculopathy, cervical myelopathy, or lumbar degenerative disease. RESULTS A total of 2770 patients (1395 males, 50.4%) were included in the analysis. The mean age at the time of surgery was 57.3 ± 14.4 years. Mean postoperative follow-up duration was 7.6 ± 6.2 months. Preoperatively, patients scored an average 15.1 ± 7.4 points below the normative population (mean 50 ± 10 points) in PF, and 15.8 ± 6.8 points above the mean in PI. PROMIS PF required a mean of 4.1 ± 0.6 questions and median 40 seconds (interquartile range [IQR] 29-58 seconds) to be completed, which was similar to PI (median 4.3 ± 1.1 questions and 38 seconds [IQR 27-59 seconds]). Patients experienced clinically meaningful improvements in PF and PI, which were sustained throughout the postoperative course. PROMIS instruments were able to capture anticipated changes in PF and PI, although to a lesser degree in PF early postoperatively. There was a strong negative correlation between PROMIS PF and PI scores at baseline (Pearson’s r = -0.72) and during follow-up appointments (early, intermediate, and late |r| > 0.6, each). Subgroup analysis demonstrated similar results within diagnostic groups compared to the overall cohort. However, the burden of PF limitations and PI was greater within the lumbar spine disease subgroup, compared to patients with cervical radiculopathy and myelopathy. CONCLUSIONS Patients receiving care at a tertiary spine surgery outpatient clinic experience significant overall disability and PI, as measured by PROMIS PF and PI computer adaptive tests. PROMIS PF and PI health domains are strongly correlated, responsive to changes over time, and facilitate time-efficient evaluations of perceived health status outcomes in patients undergoing spine surgery. © AANS 2019.

Author Keywords
Disability;  Pain interference;  Patient-reported outcomes;  Physical function;  PROMIS;  Spine

Document Type: Article
Publication Stage: Final
Source: Scopus

Median to radial nerve transfer after traumatic radial nerve avulsion in a pediatric patient
(2019) Journal of Neurosurgery: Pediatrics, 24 (2), pp. 209-214. 

Larson, E.L.^a , Santosa, K.B.^b , Mackinnon, S.E.^b , Snyder-Warwick, A.K.^b

^a Washington University School of Medicine, United States
^b Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States

Abstract
This case report describes an isolated radial nerve avulsion in a pediatric patient, treated by combination sensory and motor median to radial nerve transfers. After traumatic avulsion of the proximal radial nerve, a 12-year-old male patient underwent end-to-end transfer of median nerve branches to flexor carpi radialis and flexor digitorum superficialis to the posterior interosseous nerve and extensor carpi radialis nerve, respectively. He underwent end-to-side sensory transfer of the superficial radial sensory to the median sensory nerve. Pronator teres to extensor carpi radialis brevis tendon transfer was simultaneously performed to power short-term wrist extension. Within months after surgery, the patient had regained 9–10/10 sensation in the hand and forearm. In the following months and years, he regained dexterity, independent fine-finger and thumb motions, and 4–5/5 strength in all extensors except the abductor pollicis longus muscle. He grew 25 cm without extremity deformity or need for secondary orthopedic procedures. In appropriate adult and pediatric patients with proximal radial nerve injuries, nerve transfers have advantages over tendon transfers, including restored independent fine finger motions, regained sensation, and reinnervation of multiple muscle groups with minimal donor sacrifice. © AANS 2019, except where prohibited by US copyright law

Author Keywords
Median to radial nerve transfer;  Pediatrics;  Peripheral nerve;  Radial nerve injury

Document Type: Article
Publication Stage: Final
Source: Scopus

Life span-resolved nanotoxicology identifies nuclear amyloid, altered metabolism and neurodegenerative processes in the nematode caenorhabditis elegans
(2019) Biopolymers and Cell, 35 (3), pp. 194-195. 

Piechulek, A.^a , Scharf, A.^b , Berwanger, L.^a , Mikecz, A.V.^a

^a IUF – Leibniz Research Institute of Environmental Medicine, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany
^b Washington University, St. Louis, MO, United States

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