WashU weekly Neuroscience publications

ModCHIMERA: A novel murine closed-head model of moderate traumatic brain injury
(2018) Scientific Reports, 8 (1), art. no. 7677, . 

Sauerbeck, A.D.^a , Fanizzi, C.^{a b} , Kim, J.H.^a , Gangolli, M.^c , Bayly, P.V.^d , Wellington, C.L.^e , Brody, D.L.^a , Kummer, T.T.^a

^a Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^b Department of Neurosurgery, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
^c Department of Biomedical Engineering, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^d Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO, United States
^e Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada

Abstract
Traumatic brain injury is a major source of global disability and mortality. Preclinical TBI models are a crucial component of therapeutic investigation. We report a tunable, monitored model of murine non-surgical, diffuse closed-head injury – modCHIMERA – characterized by impact as well as linear and rotational acceleration. modCHIMERA is based on the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA) platform. We tested this model at 2 energy levels: 1.7 and 2.1 Joules – substantially higher than previously reported for this system. Kinematic analysis demonstrated linear acceleration exceeding injury thresholds in humans, although outcome metrics tracked impact energy more closely than kinematic parameters. Acute severity metrics were consistent with a complicated-mild or moderate TBI, a clinical population characterized by high morbidity but potentially reversible pathology. Axonal injury was multifocal and bilateral, neuronal death was detected in the hippocampus, and microglial neuroinflammation was prominent. Acute functional analysis revealed prolonged post-injury unconsciousness, and decreased spontaneous behavior and stimulated neurological scores. Neurobehavioral deficits were demonstrated in spatial learning/memory and socialization at 1-month. The overall injury profile of modCHIMERA corresponds with the range responsible for a substantial portion of TBI-related disability in humans. modCHIMERA should provide a reliable platform for efficient analysis of TBI pathophysiology and testing of treatment modalities. © 2018 The Author(s).

Document Type: Article
Source: Scopus

The use of continuous Erector Spinae Plane blockade for analgesia following major abdominal surgery in a one-day old neonate
(2018) Journal of Clinical Anesthesia, 49, pp. 17-18. 

Moore, R., Kaplan, I., Jiao, Y., Oster, A.

Washington University in Saint Louis School of Medicine – Department of Anesthesiology, 660 South Euclid Ave., Campus Box 8054, Saint Louis, MO, United States

Author Keywords
Neonatal anesthesia;  Pain management;  Pediatric anesthesia;  Regional analgesia

Document Type: Letter
Source: Scopus

Point-of-sale marketing and context of marijuana retailers: Assessing reliability and generalizability of the marijuana retail surveillance tool
(2018) Preventive Medicine Reports, 11, pp. 37-41. 

Berg, C.J.^a , Henriksen, L.^b , Cavazos-Rehg, P.^c , Schauer, G.L.^d , Freisthler, B.^e

^a Department of Behavioral Sciences and Health Education, Rollins School of Public Health, Emory University, 1518 Clifton Rd NE, Atlanta, GA, United States
^b Stanford Prevention Research Center, Department of Medicine, Stanford University School of Medicine, 3300 Hillview Ave, suite 120, Palo Alto, CA, United States
^c Department of Psychiatry, Washington University School of Medicine in St. Louis, 660 S. Euclid Ave., St. Louis, MO, United States
^d Department of Health Services, University of Washington, 1959 NE Pacific St, Seattle, WA, United States
^e College of Social Work, Ohio State University, 1947 College Road, Columbus, OH, United States

Abstract
As recreational marijuana expands, standardized surveillance measures examining the retail environment are critical for informing policy and enforcement. We conducted a reliability and generalizability study using a previously developed tool involving assessment of a sample of 25 randomly selected Seattle recreational marijuana retailers (20 recreational; 5 recreational/medical) in 2017. The tool assessed: 1) contextual/neighborhood features (i.e., facilities nearby); 2) compliance/security (e.g., age-of-sale signage, age verification); and 3) marketing (i.e., promotions, product availability, price). We found that retailers were commonly within two blocks of restaurants (n = 23), grocery stores (n = 17), liquor stores (n = 13), and bars/clubs (n = 11). Additionally, two were within two blocks of schools, and four were within two blocks of parks. Almost all (n = 23) had exterior signage indicating the minimum age requirement, and 23 verified age. Two retailers had exterior ads for marijuana, and 24 had interior ads. Overall, there were 76 interior ads (M = 3.04; SD = 1.84), most commonly for edibles (n = 28). At least one price promotion/discount was recorded in 17 retailers, most commonly in the form of loyalty membership programs (n = 10) or daily/weekly deals (n = 10). One retailer displayed potential health harms/warnings, while three posted some health claim. Products available across product categories were similar; we also noted instances of selling retailer-branded apparel/ paraphernalia (which is prohibited). Lowest price/unit across product categories demonstrated low variability across retailers. This study documented high inter-rater reliability of the surveillance tool (Kappas = 0.73 to 1.00). In conclusion, this tool can be used in future research and practice aimed at examining retailers marketing practices and regulatory compliance. © 2018 The Author(s)

Author Keywords
Marijuana use;  Marketing;  Measure development;  Recreational marijuana;  Retail environment

Document Type: Article
Source: Scopus
Access Type: Open Access

Internode length is reduced during myelination and remyelination by neurofilament medium phosphorylation in motor axons
(2018) Experimental Neurology, 306, pp. 158-168. 

Villalón, E.^{a b} , Barry, D.M.^c , Byers, N.^f , Frizzi, K.^e , Jones, M.R.^{a b} , Landayan, D.S.^d , Dale, J.M.^{a b} , Downer, N.L.^g , Calcutt, N.A.^e , Garcia, M.L.^{a b}

^a Department of Biological Sciences, University of Missouri, Columbia, MO, United States
^b C.S. Bond Life Sciences Center, University of Missouri, Columbia, MO, United States
^c Department of Anesthesiology, Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Quantitative and Systems Biology, University of California Merced, Merced, CA, United States
^e Department of Pathology, University of California San Diego, La Jolla, CA, United States
^f Department of Biomedical Sciences, Colorado State University, Fort Collins, CO, United States
^g Department of Biological Science, Moberly Area Community College, Moberly, MO, United States

Abstract
The distance between nodes of Ranvier, referred to as internode length, positively correlates with axon diameter, and is optimized during development to ensure maximal neuronal conduction velocity. Following myelin loss, internode length is reestablished through remyelination. However, remyelination results in short internode lengths and reduced conduction rates. We analyzed the potential role of neurofilament phosphorylation in regulating internode length during remyelination and myelination. Following ethidium bromide induced demyelination, levels of neurofilament medium (NF-M) and heavy (NF-H) phosphorylation were unaffected. Preventing NF-M lysine-serine-proline (KSP) repeat phosphorylation increased internode length by 30% after remyelination. To further analyze the role of NF-M phosphorylation in regulating internode length, gene replacement was used to produce mice in which all KSP serine residues were replaced with glutamate to mimic constitutive phosphorylation. Mimicking constitutive KSP phosphorylation reduced internode length by 16% during myelination and motor nerve conduction velocity by ~27% without altering sensory nerve structure or function. Our results suggest that NF-M KSP phosphorylation is part of a cooperative mechanism between axons and Schwann cells that together determine internode length, and suggest motor and sensory axons utilize different mechanisms to establish internode length. © 2018

Author Keywords
Axon;  Nerve injury;  Neurofilaments;  Reduced nerve conduction;  Remyelination

Document Type: Article
Source: Scopus

Alcohol use disorder and associated physical health complications and treatment amongst individuals with and without opioid dependence: A case-control study
(2018) Drug and Alcohol Dependence, 188, pp. 304-310. 

Pikovsky, M.^a , Peacock, A.^{b c} , Larney, S.^{b d} , Larance, B.^b , Conroy, E.^e , Nelson, E.^f , Degenhardt, L.^{b g h i}

^a Imperial College London, South Kensington, London, United Kingdom
^b National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW, Australia
^c School of Medicine, Department of Psychology, University of Tasmania, Hobart, TAS, Australia
^d Alpert Medical School, Brown University, 222 Richmond St., Providence, RI, United States
^e Translational Health Research Institute, Western Sydney University, Sydney, NSW, Australia
^f Department of Psychiatry, School of Medicine, Washington University, 660 S. Euclid Ave., St Louis, MO, United States
^g School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia
^h Department of Global Health, School of Public Health, University of Washington, Seattle, WA, United States
ⁱ Murdoch Children’s Research Institute, Melbourne, VIC, Australia

Abstract
Background: Dependence upon one substance may increase vulnerability for dependence on other substances. This study aimed to i) examine the association between opioid dependence and alcohol use and dependence; and ii) identify demographic, mental health, substance use, and alcohol-related withdrawal, physical health complications, and treatment correlates of comorbid alcohol and opioid dependence versus the former only. Methods: In this case-control study, 1475 participants with opioid dependence recruited from opioid substitution therapy (OST) clinics and 516 non-opioid dependent matched participants completed a structured interview covering psychiatric history, substance dependence, child maltreatment, and history of alcohol use. Analyses were mainly concentrated on cases (n = 696) and controls (n = 194) reporting lifetime alcohol dependence. Results: Cases with opioid dependence had higher rates of lifetime alcohol dependence than controls. Binary logistic regression analyses showed comorbid cases reported greater socio-economic disadvantage, poorer psychiatric history, greater incidence of dependence on other substances, earlier onset of regular drinking and alcohol dependence, and greater severity of alcohol dependence (relative to controls with alcohol dependence only). Comorbid cases were also more likely to report endorsement of certain DSM-IV criteria (i.e., legal problems due to alcohol and desire/inability to cut down use), specific withdrawal symptoms (e.g., tachycardia, hallucinations), using other substances to relieve withdrawal symptoms, and experiencing liver disease/jaundice. Rates of lifetime treatment engagement were low overall. Conclusions: Though strongly associated with alcohol dependence and alcohol-related harms, people with a history of opioid dependence have complex social and clinical backgrounds, which appear to be important factors associated with higher levels of alcohol dependence. © 2018 Elsevier B.V.

Author Keywords
Alcohol;  Alcohol dependence;  comorbidity;  Harm;  Hepatitis C;  Liver disease;  Opioid;  Opioid dependence;  Treatment

Document Type: Article
Source: Scopus

Bilateral Bow Hunter’s Syndrome Mimicking a Classic Seizure Semiology
(2018) Neurocritical Care, pp. 1-5. Article in Press. 

Albertson, A.J., Kummer, T.T.

Department of Neurology Division of Neurocritical Care, Washington University School of Medicine, 660 S. Euclid Avenue, Box 8111, St. Louis, MO, United States

Document Type: Article in Press
Source: Scopus

Patterns and predictors of tic suppressibility in youth with Tic disorders
(2018) Frontiers in Psychiatry, 9 (MAY), art. no. 188, . 

Conelea, C.A.^a , Wellen, B.^b , Woods, D.W.^c , Greene, D.J.^d , Black, K.J.^e , Specht, M.^f , Himle, M.B.^b , Lee, H.-J.^g , Capriotti, M.^{h i}

^a Department of Psychiatry, University of Minnesota, Minneapolis, MN, United States
^b Department of Psychology, University of Utah, Salt Lake City, UT, United States
^c Department of Psychology, Marquette University, Milwaukee, WI, United States
^d Departments of Psychiatry and Radiology, Washington University School of Medicine, St. Louis, MO, United States
^e Departments of Psychiatry, Neurology, Radiology, and Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
^f Weill Cornell Medical College, New York-Presbyterian Hospital-Westchester, New York, NY, United States
^g Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI, United States
^h Department of Psychology, San Jose State University, San Jose, CA, United States
ⁱ Department of Medicine, University of California, San Francisco, San Francisco, CA, United States

Abstract
Tic suppression is the primary target of tic disorder treatment, but factors that influence voluntary tic inhibition are not well understood. Several studies using the Tic Suppression Task have demonstrated significant inter-individual variability in tic suppressibility but have individually been underpowered to address correlates of tic suppression. The present study explored patterns and clinical correlates of reward-enhanced tic suppression in youth with tic disorders using a large, pooled dataset. Individual-level data from nine studies using the Tic Suppression Task were pooled, yielding a sample of 99 youth with tic disorders. Analyses examined patterns of tic suppressibility and the relationship between tic suppressibility and demographic and clinical characteristics. A large majority of youth demonstrated a high degree of tic suppression, but heterogeneous patterns of tic suppressibility were also observed. Better tic suppressibility was related to older age and more frequent tics but unrelated to other clinical variables, including presence of psychiatric comorbidity, psychotropic medication status, tic and premonitory urge severity, and self-rated tic suppressibility. The mechanisms underlying the observed heterogeneity in reward-enhanced tic suppressibility warrant further investigation. The Tic Suppression Task is a promising method for testing mechanistic hypotheses related to tic suppression. © 2018 Conelea, Wellen, Woods, Greene, Black, Specht, Himle, Lee and Capriotti.

Author Keywords
Adolescent;  Child;  Suppression;  Tic;  Tourette

Document Type: Article
Source: Scopus

Multinomial models reveal deficits of two distinct controlled retrieval processes in aging and very mild Alzheimer disease
(2018) Memory and Cognition, pp. 1-18. Article in Press. 

Millar, P.R.^a , Balota, D.A.^{a b} , Bishara, A.J.^c , Jacoby, L.L.^a

^a Department of Psychological and Brain Sciences, Washington University in St. Louis, One Brookings Drive, Campus Box 1125, St. Louis, MO, United States
^b Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Psychology, College of Charleston, Charleston, SC, United States

Abstract
Dual-process models of episodic retrieval reveal consistent deficits of controlled recollection in aging and Alzheimer disease (AD). In contrast, automatic familiarity is relatively spared. We extend standard dual-process models by showing the importance of a third capture process. Capture produces a failure to attempt recollection, which might reflect a distinct error from an inability to recollect when attempted (Jacoby et al. Journal of Experimental Psychology: General, 134(2), 131–148, 2005a). We used multinomial process tree (MPT) modeling to estimate controlled recollection and capture processes, as well as automatic retrieval processes, in a large group of middle-aged to older adults who were cognitively normal (N = 519) or diagnosed with the earliest detectable stage of AD (N = 107). Participants incidentally encoded word pairs (e.g., knee bone). At retrieval, participants completed cued word fragments (e.g., knee b_n_) with primes that were congruent (e.g., bone), incongruent (e.g., bend), or neutral (i.e., &&&) to the target (e.g., bone). MPT models estimated retrieval processes both at the group and the individual levels. A capture parameter was necessary to fit MPT models to the observed data, suggesting that dual-process models of this task can be contaminated by a capture process. In both group- and individual-level analyses, aging and very mild AD were associated with increased susceptibility to capture, decreased recollection, and no differences in automatic influences. These results suggest that it is important to consider two distinct modes of attentional control when modeling retrieval processes. Both forms of control (recollection and avoiding capture) are particularly sensitive to cognitive decline in aging and early-stage AD. © 2018 Psychonomic Society, Inc.

Author Keywords
Aging;  Attention;  Memory;  Memory models;  Recollection

Document Type: Article in Press
Source: Scopus

Molecular and Functional Sex Differences of Noradrenergic Neurons in the Mouse Locus Coeruleus
(2018) Cell Reports, 23 (8), pp. 2225-2235. 

Mulvey, B.^a , Bhatti, D.L.^b , Gyawali, S.^c , Lake, A.M.^a , Kriaucionis, S.^d , Ford, C.P.^e , Bruchas, M.R.^b , Heintz, N.^c , Dougherty, J.D.^a

^a Department of Genetics and Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Anesthesiology and Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
^c Laboratory of Molecular Biology, Rockefeller University, Howard Hughes Medical Institute, New York, NY, United States
^d Ludwig Institute for Cancer Research, University of Oxford, Oxford, United Kingdom
^e Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, United States

Abstract
Preclinical work has long focused on male animals, though biological sex clearly influences risk for certain diseases, including many psychiatric disorders. Such disorders are often treated by drugs targeting the CNS norepinephrine system. Despite roles for noradrenergic neurons in behavior and neuropsychiatric disease models, their molecular characterization has lagged. We profiled mouse noradrenergic neurons in vivo, defining over 3,000 high-confidence transcripts expressed therein, including druggable receptors. We uncovered remarkable sex differences in gene expression, including elevated expression of the EP3 receptor in females—which we leverage to illustrate the behavioral and pharmacologic relevance of these findings—and of Slc6a15 and Lin28b, both major depressive disorder (MDD)-associated genes. Broadly, we present a means of transcriptionally profiling locus coeruleus under baseline and experimental conditions. Our findings underscore the need for preclinical work to include both sexes and suggest that sex differences in noradrenergic neurons may underlie behavioral differences relevant to disease. Mulvey et al. present gene expression data from adult mouse norepinephrine neurons of the locus coeruleus (LC). They discover that over 100 genes are sex-differentially expressed in LC, including receptors, and that these receptor expression differences are substantial enough to have sex-specific consequences for LC neurons and the behaviors they control. © 2018 The Authors

Author Keywords
gene expression;  locus coeruleus;  norepinephrine;  open-field task;  sex differences;  sexual dimorphism

Document Type: Article
Source: Scopus

A composite of multisystem injury and neurocognitive impairment in HIV infection: association with everyday functioning
(2018) Journal of NeuroVirology, pp. 1-8. Article in Press. 

Marquine, M.J.^a , Flores, I.^b , Kamat, R.^a , Johnson, N.^c , Umlauf, A.^a , Letendre, S.^d , Jeste, D.^a , Grant, I.^a , Moore, D.^a , Heaton, R.K.^a

^a Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, San Diego, CA, United States
^b Neuroscience Graduate Program, University of Southern California, Los Angeles, United States
^c Department of Psychological and Brain Sciences, Washington University, Saint Louis, United States
^d Department of Medicine, University of California, San Diego, United States

Abstract
The Veterans Aging Cohort Study (VACS) Index is a composite marker of multisystem injury among HIV-infected persons. We aimed to examine its cross-sectional association with functional outcomes, after considering neurocognitive impairment (NCI) and other well-established correlates of everyday functioning among HIV-infected persons. Participants included 670 HIV-infected adults (ages 18–76; 88% male; 63% non-Hispanic White; median current CD4 = 404 cells/mm3; 67% on antiretroviral therapy; AIDS = 63%) enrolled in observational studies at the University of California San Diego HIV Neurobehavioral Research Program. Functional outcomes were assessed via self-report measures of declines in activities of daily living, perceived cognitive symptoms in daily life, and employment status. NCI was assessed via a comprehensive neurocognitive test battery and defined based on established methods. Covariates examined included demographics, HIV disease characteristics not included in the VACS Index, and psychiatric comorbidities. The VACS Index was computed via standard methods and categorized based on its distribution. Results from multivariable regression models showed that both higher VACS Index scores (indicative of worse health) and the presence of NCI were independently associated with declines in activities of daily living, increased cognitive symptoms in daily life, and unemployment. These independent effects remained after adjusting for significant covariates. In conclusion, the VACS Index may be a useful tool for identifying HIV-infected patients at high risk for everyday functioning problems. Considering factors such as NCI, historical HIV disease characteristics, and current mood might be particularly important to enhance the predictive power of the VACS Index for functional status among HIV-infected persons. © 2018 Journal of NeuroVirology, Inc.

Author Keywords
Activities of daily living;  AIDS;  Biomarkers;  Comorbidity;  Employment status;  Neurobehavioral manifestations

Document Type: Article in Press
Source: Scopus

In Vivo Characterization of Two 18F-Labeled PDE10A PET Radioligands in Nonhuman Primate Brains
(2018) ACS Chemical Neuroscience, 9 (5), pp. 1066-1073. 

Liu, H.^a , Jin, H.^b , Luo, Z.^a , Yue, X.^a , Zhang, X.^a , Flores, H.^a , Su, Y.^a , Perlmutter, J.S.^c , Tu, Z.^b

^a Department of Radiology, Physical Therapy and Occupational Therapy, Washington University, School of Medicine, St. Louis, MO, United States
^b Department of Neurology, Physical Therapy and Occupational Therapy, Washington University, School of Medicine, St. Louis, MO, United States
^c Department of Neuroscience, Physical Therapy and Occupational Therapy, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
Positron emission tomography (PET) with phosphodiesterase 10A (PDE10A) specific radioligands provides a noninvasive and quantitative imaging tool to access the expression of this enzyme in vivo under normal and diseased conditions. We recently reported two potent 18F-labeled PDE10A radioligands (18F-TZ19106B and 18F-TZ8110); initial evaluation in rats and nonhuman primates indicated stable metabolic profiles and excellent target-to-nontarget ratio (striatum/cerebellum) for both tracers. Herein, we focused on in vivo characterization of 18F-TZ19106B and 18F-TZ8110 to identify a suitable radioligand for imaging PDE10A in vivo. We directly compared microPET studies of these two radiotracers in adult male Macaca fascicularis nonhuman primates (NHPs). 18F-TZ19106B had higher striatal uptake and tracer retention in NHP brains than 18F-TZ8110, quantified by either standardized uptake values (SUVs) or nondisplaceable binding potential (BPND) estimated using reference-based modeling analysis. Blocking and displacement studies using the PDE10A inhibitor MP-10 indicated the binding of 18F-TZ19106B to PDE10A was specific and reversible. We also demonstrated sensitivity of 18F-TZ19106B binding to varying number of specific binding sites using escalating doses of MP-10 blockade (0.3, 0.5, 1.0, 1.5, and 2.0 mg/kg). Pretreatment with a dopamine D2-like receptor antagonist enhanced the striatal uptake of 18F-TZ19106B. Our results indicate that 18F-TZ19106B is a promising radioligand candidate for imaging PDE10A in vivo and it may be used to determine target engagement of PDE10A inhibitors and serve as a tool to evaluate the effect of novel antipsychotic therapies. © 2018 American Chemical Society.

Author Keywords
brain imaging;  in vivo characterization;  nonhuman primates;  PET radioligands;  Phosphodiesterase 10A;  psychotic disorders

Document Type: Article
Source: Scopus

Prefrontal Recruitment Mitigates Risk-Taking Behavior in Human Immunodeficiency Virus-Infected Young Adults
(2018) Clinical Infectious Diseases, 66 (10), pp. 1595-1601. 

Smith, R.X.^a , Guha, A.^a , Vaida, F.^b , Paul, R.H.^c , Ances, B.^a

^a Department of Neurology, Washington University in St Louis, Box 8111, 660 South Euclid Ave, Saint Louis, MO, United States
^b Division of Biostatistics and Bioinformatics, University of California, San Diego, United States
^c Missouri Institute of Mental Health, University of Missouri in St Louis, United States

Abstract
Background Human immunodeficiency virus (HIV)-infected (HIV +) young adults often engage in risk-taking behavior. However, the disruptive effects of HIV on the neurobiological underpinnings of risky decision making are not well understood. Methods Risky decision making, measured via the Iowa Gambling Task (IGT), was compared voxel-wise to resting cerebral blood flow (rCBF) acquired via arterial spin labeling. Separate topographical maps were obtained for HIV-uninfected (HIV -; n = 62) and HIV + (n = 41) young adults (18-24 years old) and were compared to the full cohort of participants. For the HIV + group, rCBF was compared to recent and nadir CD4. Results IGT performance was supported by rCBF in 3 distinct brain regions: regions I, II, and III. The relationship between IGT performance and rCBF in HIV + individuals was most robust in region I, the ventromedial prefrontal and insular cortices. Region II contained strong relationships for both HIV – and HIV +. Region III, dorsolateral prefrontal and posterior cingulate cortices, contained relationships that were strongest for HIV – controls. IGT performance was intact among HIV + participants with higher rCBF in either region I or region III. By contrast, performance was worse among HIV + individuals with lower rCBF in both regions I and III when compared to HIV – controls (P =.01). rCBF in region III was reduced in HIV + compared with HIV – individuals (P =.04), and positively associated with nadir CD4 cell count (P =.02). Conclusions Recruitment of executive systems (region III) mitigates risk-taking behavior in HIV + and HIV – individuals. Recruitment of reward systems (region I) mitigates risk-taking behavior when region III is disrupted due to immunological compromise. Identifying individual recruitment patterns may aid anatomically directed therapeutics or psychosocial interventions. © The Author(s) 2017.

Author Keywords
cerebral blood flow;  HIV;  plasticity;  risky decision making

Document Type: Article
Source: Scopus

Tau positron emission tomography in autosomal dominant Alzheimer disease small windows, big picture
(2018) JAMA Neurology, 75 (5), pp. 536-538. 

McDade, E., Bateman, R.J.

Dominantly Inherited Alzheimer Network Trials Unit, Department of Neurology, Washington University School of Medicine, 660 S Euclid Ave., St Louis, MO, United States

Document Type: Editorial
Source: Scopus

Preferential degradation of cognitive networks differentiates Alzheimer’s disease from ageing
(2018) Brain, 141 (5), pp. 1486-1500. 

Chhatwal, J.P.^{a b c} , Schultz, A.P.^{a b} , Johnson, K.A.^{a b c d} , Hedden, T.^{b d} , Jaimes, S.^a , Benzinger, T.L.S.^{e f} , Jack, C.^g , Ances, B.M.^{f h} , Ringman, J.M.ⁱ , Marcus, D.S.^{e f} , Ghetti, B.^j , Farlow, M.R.^k , Danek, A.^{l m} , Levin, J.^{m n} , Yakushev, I.^{m o} , Laske, C.^{n p} , Koeppe, R.A.^q , Galasko, D.R.^r , Xiong, C.^s , Masters, C.L.^t , Schofield, P.R.^{u v} , Kinnunen, K.M.^w , Salloway, S.^{x y} , Martins, R.N.^z , McDade, E.^h , Cairns, N.J.^h , Buckles, V.D.^h , Morris, J.C.^h , Bateman, R.^h , Sperling, R.A.^{a b c}

^a Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^b Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA, United States
^c Department of Neurology, Center for Alzheimer Research and Treatment, Brigham and Women’s Hospital, Harvard Medical School, 60 Fenwood Road, Boston, MA, United States
^d Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^e Department of Radiology, Section of Neuroradiology, Washington University, School of Medicine, St. Louis, MO, United States
^f Mallinckrodt Institute of Radiology, Washington University, School of Medicine, St Louis, MO, United States
^g Department of Radiology, Mayo Clinic, Rochester, MN, United States
^h Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
ⁱ Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
^j Department of Pathology and Laboratory Medicine, Indiana University, School of Medicine, Indianapolis, IN, United States
^k Department of Neurology, Indiana University, School of Medicine, Indianapolis, IN, United States
^l Department of Neurology, Ludwig-Maximilians Universität, Postbox 701260, Munich, Germany
^m German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
ⁿ German Center for Neurodegenerative Diseases (DZNE), Tuebingen, Germany
^o Department of Nuclear Medicine, NeuroImaging Center (TUM-NIC), Technische Universität München, Munich, Germany
^p Section for Dementia Research, Hertie Institute for Clinical Brain Research, Department of Psychiatry and Psychotherapy, University of Tuebingen, Tuebingen, Germany
^q Department of Radiology, University of Michigan, Ann Arbor, MI, United States
^r Department of Neurology, Perlman Neurology Clinic, University of California at San Diego, San Diego, CA, United States
^s Division of Biostatistics, Washington University, School of Medicine, St. Louis, MO, United States
^t Florey Institute of Neuroscience, University of Melbourne, Parkville, VIC, Australia
^u Neuroscience Research Australia, Sydney, NSW, Australia
^v School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
^w Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, United Kingdom
^x Butler Hospital, Providence, RI, United States
^y Alpert Medical School, Brown University, Providence, RI, United States
^z Centre of Excellence for Alzheimer’s Disease Research, School of Medical Sciences, Edith Cowan University, Joondalup, WA, Australia

Abstract
Converging evidence from structural, metabolic and functional connectivity MRI suggests that neurodegenerative diseases, such as Alzheimer’s disease, target specific neural networks. However, age-related network changes commonly co-occur with neuropathological cascades, limiting efforts to disentangle disease-specific alterations in network function from those associated with normal ageing. Here we elucidate the differential effects of ageing and Alzheimer’s disease pathology through simultaneous analyses of two functional connectivity MRI datasets: (i) young participants harbouring highly-penetrant mutations leading to autosomal-dominant Alzheimer’s disease from the Dominantly Inherited Alzheimer’s Network (DIAN), an Alzheimer’s disease cohort in which age-related comorbidities are minimal and likelihood of progression along an Alzheimer’s disease trajectory is extremely high; and (ii) young and elderly participants from the Harvard Aging Brain Study, a cohort in which imaging biomarkers of amyloid burden and neurodegeneration can be used to disambiguate ageing alone from preclinical Alzheimer’s disease. Consonant with prior reports, we observed the preferential degradation of cognitive (especially the default and dorsal attention networks) over motor and sensory networks in early autosomal-dominant Alzheimer’s disease, and found that this distinctive degradation pattern was magnified in more advanced stages of disease. Importantly, a nascent form of the pattern observed across the autosomal-dominant Alzheimer’s disease spectrum was also detectable in clinically normal elderly with clear biomarker evidence of Alzheimer’s disease pathology (preclinical Alzheimer’s disease). At the more granular level of individual connections between node pairs, we observed that connections within cognitive networks were preferentially targeted in Alzheimer’s disease (with between network connections relatively spared), and that connections between positively coupled nodes (correlations) were preferentially degraded as compared to connections between negatively coupled nodes (anti-correlations). In contrast, ageing in the absence of Alzheimer’s disease biomarkers was characterized by a far less network-specific degradation across cognitive and sensory networks, of between- and within-network connections, and of connections between positively and negatively coupled nodes. We go on to demonstrate that formalizing the differential patterns of network degradation in ageing and Alzheimer’s disease may have the practical benefit of yielding connectivity measurements that highlight early Alzheimer’s disease-related connectivity changes over those due to age-related processes. Together, the contrasting patterns of connectivity in Alzheimer’s disease and ageing add to prior work arguing against Alzheimer’s disease as a form of accelerated ageing, and suggest multi-network composite functional connectivity MRI metrics may be useful in the detection of early Alzheimer’s disease-specific alterations co-occurring with age-related connectivity changes. More broadly, our findings are consistent with a specific pattern of network degradation associated with the spreading of Alzheimer’s disease pathology within targeted neural networks. © The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Author Keywords
Alzheimer’s disease;  amyloid imaging;  dementia;  functional connectivity

Document Type: Article
Source: Scopus

Continuous bedside capnography monitoring of high-risk patients receiving opioids
(2018) Biomedical Instrumentation and Technology, 52 (3), pp. 208-217. 

Milligan, P.E.^{a b} , Zhang, Y.^a , Graver, S.^c

^a BJC HealthCare, St. Louis, MO, United States
^b Washington University, St. Louis, MO, United States
^c Northfield, IL, United States

Document Type: Article
Source: Scopus

Depression and long-term prognostic outcomes following peripheral endovascular interventions in the VA Healthcare System
(2018) Vascular Medicine (United Kingdom), . Article in Press. 

Smolderen, K.G.^{a b} , Plomondon, M.E.^{c d} , Armstrong, E.J.^{c d} , Hess, E.^c , Waldo, S.^{c d} , Tsai, T.T.^e , Maddox, T.M.^f

^a University of Missouri – Kansas City, Kansas City, MO, USA
^b Saint Luke’s Mid America Heart Institute, Kansas City, MO, USA
^c University of Colorado – Denver, Denver, CO, USA
^d Denver Veterans Affairs Medical Center, Denver, CO, USA
^e Kaiser Permanente, Denver, CO, USA
^f Division of Cardiology, Washington University School of Medicine, St Louis, MO, USA

Abstract
The association between depression and peripheral artery disease (PAD) outcomes remains widely understudied. In patients with PAD undergoing a peripheral vascular intervention (PVI) who have a recent diagnosis of depression, it is unknown what their long-term outcomes are and what factors may mediate an adverse risk. We therefore studied 797 consecutive patients undergoing PVI across 33 Veterans Affairs (VA) centers. Depression and outcomes were documented from patients’ medical records. Outcomes included: (1) all-cause death; (2) non-fatal cardiovascular events (myocardial infarction, stroke); and (3) PAD-related events (including repeat PVI or amputation). Cox proportional hazards frailty models were constructed, adjusting for age. Additional covariates were selected if they resulted in at least 5% change in the age-adjusted hazard ratio (HR) for depression on outcomes. Overall, 265 (33%) patients had a diagnosis of depression. After a median follow-up of 955 days (range 1–6.25 years), 52 (6.5%) patients died, 30 (3.8%) experienced non-fatal cardiovascular events, and 176 (22.1%) had PAD-related events. Compared to patients without depression, depressed patients had higher rates of non-fatal cardiovascular events (6.4% vs 2.4%, p-value 0.0055). No differences for the other outcomes were noted. Higher risk for non-fatal cardiovascular events persisted after adjustment for age (HR 1.6, 95% CI 1.05–2.47). The only additional covariate that met our selection criteria was hypertension. After adjusting for hypertension, the association between depression and non-fatal cardiovascular outcomes attenuated (HR 1.53, 95% CI 0.99–2.35). In conclusion, a diagnosis of depression in veterans undergoing PVI was associated with increased risk of non-fatal cardiovascular events, mediated by age and hypertension. © 2018, The Author(s) 2018.

Author Keywords
peripheral artery disease (PAD);  risk stratification

Document Type: Article in Press
Source: Scopus

Brain growth in the NICU: Critical periods of tissue-specific expansion
(2018) Pediatric Research, 83 (5), pp. 976-981. 

Matthews, L.G.^a , Walsh, B.H.^a , Knutsen, C.^b , Neil, J.J.^c , Smyser, C.D.^b , Rogers, C.E.^b , Inder, T.E.^a

^a Department of Pediatric Newborn Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
^b Department of Pediatrics, Washington University, Saint Louis, MO, United States
^c Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States

Abstract
ObjectiveTo examine, using serial magnetic resonance imaging (MRI), total and tissue-specific brain growth in very-preterm (VPT) infants during the period that coincides with the early and late stages of the third trimester.MethodsStructural MRI scans were collected from two prospective cohorts of VPT infants (≤30 weeks of gestation). A total of 51 MRI scans from 18 VPT subjects were available for volumetric analysis. Brain tissue was classified into cerebrospinal fluid, cortical gray matter, myelinated and unmyelinated white matter, deep nuclear gray matter, and cerebellum. Nine infants had sufficient serial scans to allow comparison of tissue growth during the periods corresponding to the early and late stages of the third trimester.ResultsTissue-specific differences in ex utero brain growth trajectories were observed in the period corresponding to the third trimester. Most notably, there was a marked increase in cortical gray matter expansion from 34 to 40 weeks of postmenstrual age, emphasizing this critical period of brain development.ConclusionUtilizing serial MRI to document early brain development in VPT infants, this study documents regional differences in brain growth trajectories ex utero during the period corresponding to the first and second half of the third trimester, providing novel insight into the maturational vulnerability of the rapidly expanding cortical gray matter in the NICU. © Copyright 2018 International Pediatric Research Foundation, Inc.

Document Type: Article
Source: Scopus

Proximity to parental symptom onset and amyloid-β burden in sporadic Alzheimer disease
(2018) JAMA Neurology, 75 (5), pp. 608-619. 

Villeneuve, S.^{a b c d j l} , Vogel, J.W.^{c d j k} , Gonneaud, J.^{c j l} , Pichet Binette, A.^{c d} , Rosa-Neto, P.^{a b c d j k l} , Gauthier, S.^{a b c j k l} , Bateman, R.J.^{e f} , Fagan, A.M.^{e f} , Morris, J.C.^{e f t} , Benzinger, T.L.S.^{f g} , Johnson, S.C.^{h i} , Breitner, J.C.S.^{a c d j l} , Poirier, J.^{a c j l} , Barkun, A.^j , Evans, A.^{c j k} , Salaciak, A.^l , Tam, A.^{c j l m} , Labonté, A.^{c l} , Faubert, A.-M.^l , Mathieu, A.^l , Courcot, B.^l , Hyman, B.T.ⁿ , Madjar, C.^{c k l} , Carrier, C.E.^l , Dansereau, C.^{m o} , Kazazian, C.^{c j l} , Tardif, C.^{c l} , Lepage, C.^{j k} , Cuello, C.^j , Debacker, C.^{c j k l} , Jack, C.R.^p , Picard, C.^{c j l} , Maillet, D.^{j l} , Fontaine, D.^{c j l} , Knopman, D.S.^p , Michaud, D.^l , Couture, D.^l , Dea, D.^{c l} , Teigner, E.^{c l} , Anthal, E.^{c l} , Yu, E.^{j l} , Vachon-Presseau, E.^{c l q} , Saint-Fort, E.F.^l , Ferdinand, F.^{c l} , Benbouhoud, F.^l , Pogossova, G.^{c l} , Maultaup, G.^j , Mayrand, G.^{c l} , Duclair, G.^{c l} , Ayranci, G.^{c j l} , Gagné, G.^{c l} , Newbold-Fox, H.^l , Leppert, I.^{c j k l} , Vallée, I.^{c l} , Near, J.^{j l} , Brandt, J.^r , Maltais, J.-R.^{c j l s} , Leoutsakos, J.-M.^r , Tremblay-Mercier, J.^{c l} , Pruessner, J.^{c j l} , Frenette, J.^{c l} , Frappier, J.^{c l} , Kat, J.^{c k l} , Miron, J.^{c j l} , Wan, K.^{c l} , Cheewakriengkrai, L.^{c j k l} , Mahar, L.^{c l} , Carmo, L.^{c l} , Münter, L.-M.^j , Collins, L.^{c k} , Théroux, L.^{c l} , Dadar, M.^{j k} , Chakravarty, M.^{c j l} , Dufour, M.^{c l} , Lafaille-Magnan, M.-E.^{c j l} , Dauar-Tedeschi, M.^{c j k l} , Sager, M.A.^u , Eisenberg, M.^j , Appleby, M.^{c l} , Savard, M.^{c l} , Tuwaig, M.^{c j l} , Petkova, M.^{c j k l} , Rajah, N.^{c j l} , Aisen, P.^v , Toussaint, P.-J.^{j k} , Kostopoulos, P.^{j k} , Bellec, P.^{c m o} , Etienne, P.^{c j l} , Tariot, P.N.^w , Orban, P.^{c l m o} , Rioux, P.^{j k} , Meyer, P.-F.^{c j l} , El-Khoury, R.^{c l} , Sperling, R.A.^x , Desautels, R.^l , Gordon, R.^{c j l} , Giles, R.^{c l} , Hoge, R.^{c k} , Thomas, R.G.^y , Das, S.^{j k} , Verfaillie, S.C.J.^{c l z} , Farzin, S.^l , Wang, S.^{j k l} , Tabrizi, S.^{c l} , Tullo, S.^{j l} , Mathotaarachchi, S.^{j k l} , Craft, S.^aa , Dubuc, S.^l , Lee, T.^{c l} , Pascoal, T.A.^{c j k l} , Montine, T.J.^ab , Beaudry, T.^{k l} , Gervais, V.^{c l} , Nair, V.^{j k l} , Bohbot, V.^{c j l} , Pagé, V.^l , Venugopalan, V.^{c l} , Fonov, V.^{j k} , Ituria-Medina, Y.^{c j k} , Khachaturian, Z.S.^ac , Presymptomatic Evaluation of Novel or Experimental Treatments for Alzheimer Disease (PREVENT-AD) Research Group^ad

^a Department of Psychiatry, McGill University, Faculty of Medicine, Douglas Mental Health University Institute, Perry Pavilion, 6875 LaSalle Blvd., Montreal, QC, Canada
^b Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
^c Douglas Mental Health University Institute, Studies on Prevention of Alzheimer’s Disease (StOP-AD) Centre, Montreal, QC, Canada
^d McGill Centre for Integrative Neuroscience, McGill University, Montreal, QC, Canada
^e Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
^f Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
^g Department of Radiology, Washington University School of Medicine, St Louis, MO, United States
^h Wisconsin Alzheimer’s Institute, University of Wisconsin-Madison School of Medicine and Public Health, Madison, United States
ⁱ Alzheimer’s Disease Research Center, University of Wisconsin-Madison School of Medicine and Public Health, Madison, United States
^j McGill University, Montreal, QC, Canada
^k Montreal Neurological Institute and Hospital, Montreal, QC, Canada
^l Douglas Mental Health University Institute Research Centre, Affiliated with McGill University, Montreal, QC, Canada
^m Centre de Recherche, Institut Universitaire de Gériatrie, Montreal, QC, Canada
ⁿ Massachussets Alzheimer’s Disease Research Center, Harvard Medical School, Boston, MA, United States
^o Université de Montréal, Montreal, QC, Canada
^p Mayo Clinic, Rochester, MN, United States
^q Northwestern University, Chicago, IL, United States
^r Johns Hopkins University, Baltimore, MD, United States
^s McGill University Research Centre for Studies in Aging, Montreal, QC, Canada
^t Washington University School of Medicine, St Louis, MO, United States
^u Wisconsin Alzheimer’s Institute, University of Wisconsin School of Medicine and Public Health, Milwaukee, United States
^v University of Southern California’s Alzheimer’s Therapeutic Research Institute, San Diego, United States
^w Banner Alzheimer Institute, Phoenix, AZ, United States
^x Center for Alzheimer’s Research and Treatment, Harvard Medical School, Boston, MA, United States
^y University of California, San Diego, School of Medicine, San Diego, United States
^z Alzheimer Center, VU University Amsterdam, Amsterdam, Netherlands
^aa Wake Forest School of Medicine, Winston-Salem, NC, United States
^ab Washington University, Seattle, United States
^ac Khachaturian and Associates Inc., Potomac, MD, United States

Abstract
IMPORTANCE Alzheimer disease (AD) develops during several decades. Presymptomatic individuals might be the best candidates for clinical trials, but their identification is challenging because they have no symptoms. OBJECTIVE To assess whether a sporadic parental estimated years to symptom onset calculation could be used to identify information about amyloid-β (Aβ) levels in asymptomatic individuals with a parental history of AD dementia. DESIGN, SETTING, AND PARTICIPANTS This cohort study analyzed Aβ1-42 in cerebrospinal fluid (CSF) specimens from 101 cognitively normal individuals who had a lumbar puncture as part of the Presymptomatic Evaluation of Novel or Experimental Treatments for Alzheimer Disease (PREVENT-AD) cohort from September 1, 2011, through November 30, 2016 (374 participants were enrolled in the cohort during this period). The study estimated each participant’s proximity to his/her parent’s symptom onset by subtracting the index relative’s onset age from his/her current age. The association between proximity to parental symptom onset and Aβ levels was then assessed using apolipoprotein E ϵ4 (APOE4) status and sex as interactive terms. These analyses were performed again in 2 independent cohorts using CSF and Pittsburgh compound B carbon 11-labeled positron emission tomography (PIB-PET) Aβ biomarkers: the Adult Children Study (ACS) and the Wisconsin Registry for Alzheimer Prevention (WRAP) cohorts. MAIN OUTCOMES AND MEASURES The association between proximity to parental symptom onset and Aβ burden in asymptomatic individuals with a parental history of sporadic AD. RESULTS The present analysis included a subset of 101 PREVENT-AD individuals (mean [SD] age, 61.8 [5.1] years; 30 [29.7%] male), 128 ACS participants (112 participants underwent CSF measurement: mean [SD] age, 63.4 [5.1] years; 31 [27.7%] male; and 107 underwent PIB-PET: mean [SD] age, 64.6 [5.3] years; 27 [25.2%] male), and 135 WRAP participants (85 participants underwent CSF measurement: mean [SD] age, 59.9 [6.0] years; 27 [31.8%] male; and 135 underwent PIB-PET: mean [SD] age, 59.6 [6.1] years; 43 [31.9%] male). In the PREVENT-AD cohort, individuals approaching their parent’s onset age had lower CSF Aβ1-42 levels (range, 402-1597; B = -9.09, P = .04). This association was stronger in APOE4 carriers (B = -17.9, P = .03) and women (B = -19.8, P = .02). In the ACS cohort, the main association was replicated using PIB-PET data, and the sex interaction was replicated using CSF and PIB-PET data. In the WRAP cohort, the results were not replicated using cross-sectional data, but the main association and the APOE interaction were replicated using PIB-PET longitudinal data. CONCLUSIONS AND RELEVANCE These results suggest that proximity to parental symptom onsetmay help estimate Aβ biomarker changes in women or APOE4 carrier asymptomatic individuals with a parental history of sporadic AD. © 2018 American Medical Association. All rights reserved.

Document Type: Article
Source: Scopus

MED13L-related intellectual disability: involvement of missense variants and delineation of the phenotype
(2018) Neurogenetics, 19 (2), pp. 93-103. 

Smol, T.^{a b} , Petit, F.^{b c} , Piton, A.^d , Keren, B.^e , Sanlaville, D.^f , Afenjar, A.^g , Baker, S.^h , Bedoukian, E.C.ⁱ , Bhoj, E.J.^h , Bonneau, D.^j , Boudry-Labis, E.^a , Bouquillon, S.^a , Boute-Benejean, O.^{b c} , Caumes, R.^c , Chatron, N.^f , Colson, C.^{b c} , Coubes, C.^k , Coutton, C.^l , Devillard, F.^l , Dieux-Coeslier, A.^{b c} , Doco-Fenzy, M.^m , Ewans, L.J.ⁿ , Faivre, L.^{o p} , Fassi, E.^q , Field, M.^r , Fournier, C.^d , Francannet, C.^s , Genevieve, D.^k , Giurgea, I.^t , Goldenberg, A.^u , Green, A.K.^v , Guerrot, A.M.^u , Heron, D.^e , Isidor, B.^w , Keena, B.A.^x , Krock, B.L.^h , Kuentz, P.^p , Lapi, E.^y , Le Meur, N.^u , Lesca, G.^f , Li, D.^h , Marey, I.^e , Mignot, C.^e , Nava, C.^e , Nesbitt, A.^h , Nicolas, G.^u , Roche-Lestienne, C.^a , Roscioli, T.ⁿ , Satre, V.^l , Santani, A.^h , Stefanova, M.^v , Steinwall Larsen, S.^v , Saugier-Veber, P.^u , Picker-Minh, S.^z , Thuillier, C.^a , Verloes, A.^aa , Vieville, G.^l , Wenzel, M.^x , Willems, M.^k , Whalen, S.^e , Zarate, Y.A.^ab , Ziegler, A.^j , Manouvrier-Hanu, S.^{b c} , Kalscheuer, V.M.^ac , Gerard, B.^d , Ghoumid, J.^{b c}

^a Institut de Génétique Médicale, Hôpital Jeanne de Flandre, CHU Lille, Lille, France
^b University of Lille, EA 7364-RADEME, Lille, France
^c Service de Génétique Clinique, Hôpital Jeanne de Flandre, CHU Lille, avenue Eugène Avinée, Lille, France
^d Laboratoire de diagnostic génétique, Institut de Génétique Médicale d’Alsace, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
^e Département de Génétique, Groupe Hospitalier Pitié-Salpêtrière, AP-HP, Paris, France
^f Service de Génétique, Hospices Civils de Lyon, Lyon, France
^g Service de Génétique, Hôpital d’Enfants Armand-Trousseau, AP-HP, Paris, France
^h Department of Pathology Laboratory Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
ⁱ Roberts Individualized Medical Genetics Center, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^j Service de Génétique, CHU d’Angers, Angers, France
^k Département de Génétique Médicale, CHU Montpellier, Montpellier, France
^l Laboratoire de Génétique Chromosomique, CHU Grenoble Alpes, Grenoble, France
^m Service de Génétique, EA3801, SFR-CAP Santé, CHU de Reims, Reims, France
ⁿ St Vincent’s Clinical School, University of New South Wales, Darlinghurst, NSW, Australia
^o Centre de Génétique et Centre de Référence Maladies Rares ‘Anomalies du Développement, CHU Dijon, Dijon, France
^p Equipe GAD, UMR INSERM 1231, Université de Bourgogne, Dijon, France
^q Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^r The Genetics of Learning Disability Service, Waratah, NSW, Australia
^s Service de Génétique Médicale, CHU de Clermont-Ferrand, Clermont-Ferrand, France
^t Service de Génétique, Hôpital Trousseau, AP-HP, Paris, France
^u Service de Génétique et Inserm U1079, Centre Normand de Génomique Médicale et Médecine Personnalisée, CHU de Rouen, Inserm et Université de Rouen, Rouen, France
^v Department of Clinical Genetics, University Hospital Linköping, Linköping, Sweden
^w Service de Génétique Médicale, Unité de Génétique Clinique, CHU de Nantes, Nantes, France
^x Clinical Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^y Medical Genetics Unit, Anna Meyer Children’s University Hospital, Florence, Italy
^z Department of Pediatric Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany
^aa Unité Fonctionnelle de Génétique Clinique, Hôpital Robert Debré, AP-HP, Paris, France
^ab Section of Genetics and Metabolism, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, United States
^ac Research Group Development and Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany

Abstract
Molecular anomalies in MED13L, leading to haploinsufficiency, have been reported in patients with moderate to severe intellectual disability (ID) and distinct facial features, with or without congenital heart defects. Phenotype of the patients was referred to “MED13L haploinsufficiency syndrome.” Missense variants in MED13L were already previously described to cause the MED13L-related syndrome, but only in a limited number of patients. Here we report 36 patients with MED13L molecular anomaly, recruited through an international collaboration between centers of expertise for developmental anomalies. All patients presented with intellectual disability and severe language impairment. Hypotonia, ataxia, and recognizable facial gestalt were frequent findings, but not congenital heart defects. We identified seven de novo missense variations, in addition to protein-truncating variants and intragenic deletions. Missense variants clustered in two mutation hot-spots, i.e., exons 15–17 and 25–31. We found that patients carrying missense mutations had more frequently epilepsy and showed a more severe phenotype. This study ascertains missense variations in MED13L as a cause for MED13L-related intellectual disability and improves the clinical delineation of the condition. © 2018, Springer-Verlag GmbH Germany, part of Springer Nature.

Author Keywords
Cardiopathy;  Intellectual disability;  MED13L;  Mediator complex

Document Type: Article
Source: Scopus

Graph complexity analysis identifies an ETV5 tumor-specific network in human and murine low-grade glioma
(2018) PLoS ONE, 13 (5), art. no. e0190001, . 

Pan, Y.^a , Duron, C.^b , Bush, E.C.^c , Ma, Y.^a , Sims, P.A.^c , Gutmann, D.H.^a , Radunskaya, A.^d , Hardin, J.^d

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Mathematics, Claremont Graduate University, Claremont, California, United States
^c Departments of Systems Biology and of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, New York, United States
^d Department of Mathematics, Pomona College, Claremont, CA, United States

Abstract
Conventional differential expression analyses have been successfully employed to identify genes whose levels change across experimental conditions. One limitation of this approach is the inability to discover central regulators that control gene expression networks. In addition, while methods for identifying central nodes in a network are widely implemented, the bioinformatics validation process and the theoretical error estimates that reflect the uncertainty in each step of the analysis are rarely considered. Using the betweenness centrality measure, we identified Etv5 as a potential tissue-level regulator in murine neurofibromatosis type 1 (Nf1) low-grade brain tumors (optic gliomas). As such, the expression of Etv5 and Etv5 target genes were increased in multiple independently-generated mouse optic glioma models relative to non-neoplastic (normal healthy) optic nerves, as well as in the cognate human tumors (pilocytic astrocytoma) relative to normal human brain. Importantly, differential Etv5 and Etv5 network expression was not directly the result of Nf1 gene dysfunction in specific cell types, but rather reflects a property of the tumor as an aggregate tissue. Moreover, this differential Etv5 expression was independently validated at the RNA and protein levels. Taken together, the combined use of network analysis, differential RNA expression findings, and experimental validation highlights the potential of the computational network approach to provide new insights into tumor biology. © 2018 Pan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Document Type: Article
Source: Scopus

Data-driven models of dominantly-inherited Alzheimer’s disease progression
(2018) Brain, 141 (5), pp. 1529-1544. Cited 1 time.

Oxtoby, N.P.^a , Young, A.L.^a , Cash, D.M.^{b c} , Benzinger, T.L.S.^d , Fagan, A.M.^d , Morris, J.C.^d , Bateman, R.J.^d , Fox, N.C.^{b e} , Schott, J.M.^b , Alexander, D.C.^a

^a Progression of Neurodegenerative Disease Group, Centre for Medical Image Computing, Department of Computer Science, University College London, Gower Street, London, United Kingdom
^b Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, 8-11 Queen Square, London, United Kingdom
^c Translational Imaging Group, Centre for Medical Image Computing, Department of Medical Physics and Biomedical Engineering, University College London, Gower Street, London, United Kingdom
^d Department of Neurology, Washington University, School of Medicine, St Louis, MO, United States
^e UK Dementia Research Institute, University College London, London, United Kingdom

Abstract
See Li and Donohue (doi:10.1093/brain/awy089) for a scientific commentary on this article. Dominantly-inherited Alzheimer’s disease is widely hoped to hold the key to developing interventions for sporadic late onset Alzheimer’s disease. We use emerging techniques in generative data-driven disease progression modelling to characterize dominantly-inherited Alzheimer’s disease progression with unprecedented resolution, and without relying upon familial estimates of years until symptom onset. We retrospectively analysed biomarker data from the sixth data freeze of the Dominantly Inherited Alzheimer Network observational study, including measures of amyloid proteins and neurofibrillary tangles in the brain, regional brain volumes and cortical thicknesses, brain glucose hypometabolism, and cognitive performance from the Mini-Mental State Examination (all adjusted for age, years of education, sex, and head size, as appropriate). Data included 338 participants with known mutation status (211 mutation carriers in three subtypes: 163 PSEN1, 17 PSEN2, and 31 APP) and a baseline visit (age 19-66; up to four visits each, 1.1 ± 1.9 years in duration; spanning 30 years before, to 21 years after, parental age of symptom onset). We used an event-based model to estimate sequences of biomarker changes from baseline data across disease subtypes (mutation groups), and a differential equation model to estimate biomarker trajectories from longitudinal data (up to 66 mutation carriers, all subtypes combined). The two models concur that biomarker abnormality proceeds as follows: amyloid deposition in cortical then subcortical regions (∼ 24 ± 11 years before onset); phosphorylated tau (17 ± 8 years), tau and amyloid-β changes in cerebrospinal fluid; neurodegeneration first in the putamen and nucleus accumbens (up to 6 ± 2 years); then cognitive decline (7 ± 6 years), cerebral hypometabolism (4 ± 4 years), and further regional neurodegeneration. Our models predicted symptom onset more accurately than predictions that used familial estimates: root mean squared error of 1.35 years versus 5.54 years. The models reveal hidden detail on dominantly-inherited Alzheimer’s disease progression, as well as providing data-driven systems for fine-grained patient staging and prediction of symptom onset with great potential utility in clinical trials. © The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Author Keywords
biomarker dynamics;  differential-equation model;  disease progression;  dominantly-inherited Alzheimer’s disease;  event-based model

Document Type: Article
Source: Scopus

Linear-array based full-view high-resolution photoacoustic computed tomography of whole mouse brain functions in vivo
(2018) Progress in Biomedical Optics and Imaging – Proceedings of SPIE, 10494, art. no. 104941H, . 

Li, L.^a , Zhang, P.^b , Wang, L.V.^a

^a Caltech Optical Imaging Laboratory, Andrew and Peggy Cherng Department of Medical Engineering, Department of Electrical Engineering, California Institute of Technology, 1200 E California Blvd., Pasadena, CA, United States
^b Department of Biomedical Engineering, Washington University in St. Louis, One Brookings Dr., St. Louis, MO, United States

Abstract
Photoacoustic computed tomography (PACT) is a non-invasive imaging technique offering high contrast, high resolution, and deep penetration in biological tissues. We report a photoacoustic computed tomography (PACT) system equipped with a high frequency linear array for anatomical and functional imaging of the mouse whole brain. The linear array was rotationally scanned in the coronal plane to achieve the full-view coverage. We investigated spontaneous neural activities in the deep brain by monitoring the hemodynamics and observed strong interhemispherical correlations between contralateral regions, both in the cortical layer and in the deep regions. © COPYRIGHT SPIE. Downloading of the abstract is permitted for personal use only.

Author Keywords
deep brain imaging;  functional imaging;  Photoacoustic computed tomography

Document Type: Conference Paper
Source: Scopus

A Population-Based Assessment of Depression and Anxiety in Patients With Brachial Plexus Injuries
(2018) Journal of Hand Surgery, . Article in Press. 

Yannascoli, S.M.^a , Stwalley, D.^a , Saeed, M.J.^b , Olsen, M.A.^a , Dy, C.J.^a

^a Division of Hand and Microsurgery, Department of Orthopaedic Surgery, Washington University School of Medicine, St Louis, MO, United States
^b Capital Health, Trenton, NJ, United States

Abstract
Purpose: Reactive depression and anxiety are common after major life changes such as brachial plexus injuries (BPI). The purpose of this study was to evaluate the incidence and risk factors for coded depression and coded anxiety among patients with BPI using a national database of commercial insurance claims. Methods: We used the Truven MarketScan database from 2007 to 2013 to identify commercially insured patients aged 18 to 64 years who underwent BPI surgery. For comparison, a control group without BPI was frequency-matched 10:1 by age group, sex, number of provider visits, and length of insurance enrollment. Using International Classification of Diseases, Ninth Revision diagnosis codes and pharmacy claims, we identified coded depression and coded anxiety in the 12 months before and 12 months after BPI surgery. Multivariable Cox regression models were used to determine risk factors for coded depression or coded anxiety, adjusting for known risk factors for depression or anxiety (eg, alcohol, substance abuse). Results: We identified 1,843 patients with BPI and 18,430 controls. Within the 12 months preceding surgery, coded depression and coded anxiety were present in 38% and 42%, respectively, of the BPI group; both were present in 25% and either was present in 54%. The rate of new-onset/postoperatively coded depression among patients with BPI was 142.1/1,000 person-years (12%) and of new-onset/postoperatively coded anxiety was 273.6/1,000 person-years (20%). Patients with BPI were significantly more likely than controls to develop new-onset/postoperatively coded depression (hazard ratio = 1.3; confidence interval [CI], 1.1–1.5) and new-onset/postoperatively coded anxiety (HR = 2.1 [CI, 1.8–2.4]). Conclusions: Patients undergoing BPI surgery have a high prevalence of coded depression and coded anxiety in the 12 months before surgery and are at higher risk for developing new-onset/postoperatively coded depression and coded anxiety within 1 year after surgery. These findings can be used by BPI surgeons to inform perioperative counseling, guide emotional recovery from injury, and facilitate coordinated or colocated care with mental health professionals. Type of study/level of evidence: Prognostic II. © 2018 American Society for Surgery of the Hand

Author Keywords
Anxiety;  brachial plexus;  depression;  mental health;  nerve injury

Document Type: Article in Press
Source: Scopus

Convolutional neural network based automatic plaque characterization for intracoronary optical coherence tomography images
(2018) Progress in Biomedical Optics and Imaging – Proceedings of SPIE, 10574, art. no. 1057432, . 

He, S.^a , Zheng, J.^b , Maehara, A.^e , Mintz, G.^e , Tang, D.^f , Anastasio, M.^{a b c d} , Li, H.^c

^a Department of Computer Science and Engineering, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Radiology, Washington University, School of Medicine, St. Louis, MO, United States
^c Department of Radiation Oncology, Washington University, School of Medicine, St. Louis, MO, United States
^d Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
^e Cardiovascular Research Foundation, New York, NY, United States
^f Worcester Polytechhic Institute, Worcester, MA, United States

Abstract
Optical coherence tomography (OCT) can provide high-resolution cross-sectional images for analyzing superficial plaques in coronary arteries. Commonly, plaque characterization using intra-coronary OCT images is performed manually by expert observers. This manual analysis is time consuming and its accuracy heavily relies on the experience of human observers. Traditional machine learning based methods, such as the least squares support vector machine and random forest methods, have been recently employed to automatically characterize plaque regions in OCT images. Several processing steps, including feature extraction, informative feature selection, and final pixel classification, are commonly used in these traditional methods. Therefore, the final classification accuracy can be jeopardized by error or inaccuracy within each of these steps. In this study, we proposed a convolutional neural network (CNN) based method to automatically characterize plaques in OCT images. Unlike traditional methods, our method uses the image as a direct input and performs classification as a single- step process. The experiments on 269 OCT images showed that the average prediction accuracy of CNN-based method was 0.866, which indicated a great promise for clinical translation. © COPYRIGHT SPIE. Downloading of the abstract is permitted for personal use only.

Author Keywords
automatic plaque characterization;  Convolutional neural network;  optical coherence tomography

Document Type: Conference Paper
Source: Scopus

Bdnf variant is associated with milder motor symptom severity in early-stage Parkinson’s disease
(2018) Parkinsonism and Related Disorders, . Article in Press. 

Fischer, D.L.^a , Auinger, P.^b , Goudreau, J.L.^c , Paumier, K.L.^{a e} , Cole-Strauss, A.^a , Kemp, C.J.^a , Lipton, J.W.^{a d} , Sortwell, C.E.^{a d}

^a Department of Translational Science & Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States
^b Center for Health and Technology, Department of Neurology, University of Rochester, Rochester, NY, United States
^c Department of Neurology and Ophthalmology, College of Osteopathic Medicine, Michigan State University, East Lansing, MI, United States
^d Mercy Health Saint Mary’s, Grand Rapids, MI, United States
^e Department of Neurology, Washington University, Saint Louis, MO, United States

Abstract
Introduction: Parkinson’s disease (PD) progression is heterogeneous. Variants in PD-related genes may alter disease progression or severity. We examined if the single nucleotide variant rs6265 in the gene Bdnf alters clinical phenotype in early-stage, unmedicated PD. Methods: A retrospective analysis was conducted using data collected in the Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism (DATATOP) study. DNA samples (n = 217) were genotyped for the Bdnf rs6265 variant, and the primary endpoint was time to initiate levodopa. The Parkinson’s Progression Markers Initiative (PPMI) was used for validation (n = 383). Results: The primary endpoint of time to initiate levodopa was associated with a delay in subjects with two copies of the rs6265 minor (Met66) allele (HR: 4.9; 95% CI: 1.3–18.8). Secondary endpoints were not different among genotypes. PPMI subjects with two Met66 alleles demonstrated significantly lower total and part III Movement Disorder Society – United Parkinson’s Disease Rating Scale (MDS-UPDRS) scores at baseline, as well as more tremor-related symptoms, but not a delay in initiation of maintenance pharmacotherapy. Conclusions: Data from two distinct, unmedicated, early-stage PD cohorts suggest that carrying two copies of the rs6265 Met66 allele (∼4% of the population) is associated with less severity in motor symptoms and potentially a slower rate of progression. © 2018

Author Keywords
Brain-derived neurotrophic factor;  Levodopa;  rs6265;  Single nucleotide polymorphism;  Val66Met

Document Type: Article in Press
Source: Scopus

A Fine-Scale Functional Logic to Convergence from Retina to Thalamus
(2018) Cell, 173 (6), pp. 1343-1355.e24. 

Liang, L.^{a b} , Fratzl, A.^{a c f} , Goldey, G.^a , Ramesh, R.N.^{a d} , Sugden, A.U.^a , Morgan, J.L.^e , Chen, C.^{b d} , Andermann, M.L.^{a d}

^a Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
^b F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
^c Laboratory of Synaptic Mechanisms, Brain Mind Institute, School of Life Science, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
^d Program in Neuroscience, Harvard Medical School, Boston, MA, United States
^e Department of Ophthalmology and Visual Sciences, Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
^f Sainsbury Wellcome Centre for Neural Circuits and Behaviour, University College London, London, United Kingdom

Abstract
Numerous well-defined classes of retinal ganglion cells innervate the thalamus to guide image-forming vision, yet the rules governing their convergence and divergence remain unknown. Using two-photon calcium imaging in awake mouse thalamus, we observed a functional arrangement of retinal ganglion cell axonal boutons in which coarse-scale retinotopic ordering gives way to fine-scale organization based on shared preferences for other visual features. Specifically, at the ∼6 μm scale, clusters of boutons from different axons often showed similar preferences for either one or multiple features, including axis and direction of motion, spatial frequency, and changes in luminance. Conversely, individual axons could “de-multiplex” information channels by participating in multiple, functionally distinct bouton clusters. Finally, ultrastructural analyses demonstrated that retinal axonal boutons in a local cluster often target the same dendritic domain. These data suggest that functionally specific convergence and divergence of retinal axons may impart diverse, robust, and often novel feature selectivity to visual thalamus. Selective clustering of retinal ganglion cell axonal boutons that share one or multiple visual feature preferences in common may promote diverse and often novel channels of visual information in target dendrites in thalamus. © 2018 Elsevier Inc.

Author Keywords
chronic two-photon calcium imaging in awake mice;  combination mode;  divergence;  dorsal lateral geniculate nucleus;  presynaptic functional clustering;  relay mode;  retinal boutons;  retinal ganglion cell;  visual processing;  visual tuning

Document Type: Article
Source: Scopus

Longitudinal assessment of hippocampus structure in children with type 1 diabetes
(2018) Pediatric Diabetes, . Article in Press. 

Foland-Ross, L.C.^a , Reiss, A.L.^{a b c} , Mazaika, P.K.^a , Mauras, N.^d , Weinzimer, S.A.^e , Aye, T.^{a f} , Tansey, M.J.^g , White, N.H.^h

^a Department of Psychiatry and Behavioral Sciences, Center for Interdisciplinary Brain Sciences Research Stanford University Stanford, California
^b Department of Pediatrics Stanford University School of Medicine Stanford, California
^c Department of Radiology Stanford University School of Medicine Stanford, California
^d Pediatric Endocrinology Nemours Children’s Health System Jacksonville, Florida
^e Pediatric Endocrinology Yale University New Haven, Connecticut
^f Division of Pediatric Endocrinology Stanford School of Medicine Stanford, California
^g Department of Pediatric Endocrinology University of Iowa Iowa City, Iowa
^h Department of Pediatrics Washington University in St. Louis and the St. Louis Children’s Hospital St. Louis, Missouri

Abstract
The extant literature finds that children with type 1 diabetes mellitus (T1D) experience mild cognitive alterations compared to healthy age-matched controls. The neural basis of these cognitive differences is unclear but may relate in part to the effects of dysglycemia on the developing brain. We investigated longitudinal changes in hippocampus volume in young children with early-onset T1D. Structural magnetic resonance imaging data were acquired from 142 children with T1D and 65 age-matched control subjects (4-10years of age at study entry) at 2 time points, 18 months apart. The effects of diabetes and glycemic exposure on hippocampal volume and growth were examined. Results indicated that although longitudinal hippocampus growth did not differ between children with T1D and healthy control children, slower growth of the hippocampus was associated with both increased exposure to hyperglycemia (interval HbA1c) and greater glycemic variability (MAGE) in T1D. These observations indicate that the current practice of tolerating some hyperglycemia to minimize the risk of hypoglycemia in young children with T1D may not be optimal for the developing brain. Efforts that continue to assess the factors influencing neural and cognitive development in children with T1D will be critical in minimizing the deleterious effects of diabetes. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Author Keywords
Blood glucose;  Brain;  Hippocampus;  Hyperglycemia;  Type 1 diabetes mellitus

Document Type: Article in Press
Source: Scopus

Improving pediatricians’ knowledge and skills in suicide prevention: Opportunities for social work
(2018) Qualitative Social Work, . Article in Press. 

Behrman, G.U.^a , Secrest, S.^b , Ballew, P.^a , Matthieu, M.M.^c , Glowinski, A.L.^d , Scherrer, J.F.^b

^a CHADS Coalition for Mental Health, Saint Louis University, St. Louis, USA
^b Department of Family and Community Medicine, Saint Louis University School of Medicine, St. Louis, USA
^c School of Social Work, Saint Louis University, St. Louis, USA
^d Department of Psychiatry, Washington University School of Medicine, St. Louis, USA

Abstract
Primary care physicians are key gatekeepers for detecting suicidal intent. However, research indicates training gaps for these providers. Standardized screening for suicide risk in primary care can detect youth with suicidal ideation and prompt a referral to behavioral health care before a suicide attempt. What is needed in adolescent primary care is further training in utilizing standardized mental health screening and employing best practices for suicide prevention. In this study, qualitative research methods were used in surfacing community and medical perspectives regarding skills, knowledge, and values that are needed in pediatric medicine to adequately assess for depression and anxiety. Five focus groups were conducted with pediatric residents, adolescents, parents of adolescents who died by suicide, parents with adolescents in the mental health system, and community mental health professionals. Four themes were identified that illustrate what is needed in pediatric training to lower the risks for adolescent suicide: broken mental health system of care; improving doctor/patient/family communication; alleviating stigma; and early detection and treatment that addresses medications, substance abuse, and recovery resources. The goals of this grant funded study were to analyze the data from these focus groups and compare findings across groups to create modules for Saint Louis University pediatric resident training in suicide prevention. This research project can serve as a springboard for social workers to partner with medical educators in their communities to train primary care physicians for early detection of depression, anxiety, and substance abuse to lower adolescent suicide risks. © 2018, The Author(s) 2018.

Author Keywords
adolescents;  Education;  suicide prevention

Document Type: Article in Press
Source: Scopus

Implementing Motor Unit Number Index (MUNIX) in a large clinical trial: Real world experience from 27 centres
(2018) Clinical Neurophysiology, . Article in Press. 

Neuwirth, C.^a , Braun, N.^a , Claeys, K.G.^{b c} , Bucelli, R.^d , Fournier, C.^e , Bromberg, M.^f , Petri, S.^g , Goedee, S.^h , Lenglet, T.ⁱ , Leppanen, R.^j , Canosa, A.^k , Goodman, I.^l , Al-Lozi, M.^d , Ohkubo, T.^m , Hübers, A.ⁿ , Atassi, N.^o , Abrahao, A.^p , Funke, A.^q , Appelfeller, M.^r , Tümmler, A.^r , Finegan, E.^s , Glass, J.D.^e , Babu, S.^o , Ladha, S.S.^t , Kwast-Rabben, O.^u , Juntas-Morales, R.^v , Coffey, A.^s , Chaudhry, V.^w , Vu, T.^x , Saephanh, C.^y , Newhard, C.^z , Zakrzewski, M.^z , Rosier, E.^aa , Hamel, N.^aa , Raheja, D.^ab , Raaijman, J.^h , Ferguson, T.^ac , Weber, M.^{a ad}

^a Neuromuscular Diseases Unit/ALS Clinic, Kantonsspital St. Gallen, St. Gallen, Switzerland
^b Department of Neurology, Neuromuscular Reference Centre, University Hospitals Leuven, Leuven, Belgium
^c Laboratory for Muscle Diseases and Neuropathies, Department of Neurosciences, Experimental Neurology, KU Leuven, Leuven, Belgium
^d Washington University School of Medicine, Department of Neurology, Washington, United States
^e Emory University, Department of Neurology, Atlanta, United States
^f Clinical Neurosciences Center, Salt Lake City, United States
^g Department of Neurology, Hannover Medical School, Hannover, Germany
^h Brain Centre Rudolf Magnus, Department of Neurology and Neurosurgery, UMC Utrecht, Utrecht, Netherlands
ⁱ Département de Neurophysiologie, Groupe hospitalier Pitié-Salpêtrière, APHP, Paris, France
^j University Neurology and Cole Neuroscience Center, University of Tennessee, Knoxville, United States
^k ALS Center of Torino, Department of Neuroscience “Rita Levi Montalcini”, University of Torino, Torino, Italy
^l BioClinica Research Orlando, United States
^m ALS Clinical and Translational Research, University of California, San Diego, United States
ⁿ Department of Neurology, University of Ulm, Ulm, Germany
^o Neurological Clinical Research Institute (NCRI), Department of Neurology, Massachusetts General Hospital, Boston, United States
^p Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada
^q Charité – Universitätsmedizin Berlin, Outpatient Center for ALS and Other Motor Neuron Disorders, Berlin, Germany
^r Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany
^s Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland
^t Department of Neurology, Barrow Neurological Institute, Phoenix, United States
^u Department of Pharmacology and Clinical Neuroscience, Umeå, Sweden
^v Département de Neurologie, CHU de Montpellier, Montpellier, France
^w Johns Hopkins University School of Medicine, Baltimore, United States
^x Neuromuscular Division, University of South Florida, Tampa, United States
^y California Pacific Medical Center Research Institute, San Francisco, United States
^z East Campus Health Center, Neurophysiology Department, Hershey, United States
^aa Montreal Neurological Institute and Hospital, Montreal, Canada
^ab Penn State Medical Center Neuroscience Institute, Morgantown, United States
^ac Biogen, United States
^ad Department of Neurology, University Hospital Basel, Basel, Switzerland

Abstract
Objective: Motor Unit Number Index (MUNIX) is a quantitative neurophysiological method that reflects loss of motor neurons in Amyotrophic Lateral Sclerosis (ALS) in longitudinal studies. It has been utilized in one natural history ALS study and one drug trial (Biogen USA) after training and qualification of raters. Methods: Prior to testing patients, evaluators had to submit test-retest data of 4 healthy volunteers. Twenty-seven centres with 36 raters measured MUNIX in 4 sets of 6 different muscles twice. Coefficient of variation of all measurements had to be <20% to pass the qualification process. MUNIX COV of the first attempt, number of repeated measurements and muscle specific COV were evaluated. Results: COV varied considerably between raters. Mean COV of all raters at the first measurements was 12.9% ± 13.5 (median 8.7%). Need of repetitions ranged from 0 to 43 (mean 10.7 ± 9.1, median 8). Biceps and first dorsal interosseus muscles showed highest repetition rates. MUNIX variability correlated considerably with variability of compound muscle action potential. Conclusion: MUNIX revealed generally good reliability, but was rater dependent and ongoing support for raters was needed. Significance: MUNIX can be implemented in large clinical trials as an outcome measure after training and a qualification process. © 2018 International Federation of Clinical Neurophysiology

Author Keywords
Implementation;  Multicentre;  MUNIX;  Training;  Variability

Document Type: Article in Press
Source: Scopus

Intraoperative ketamine for prevention of depressive symptoms after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial
(2018) British Journal of Anaesthesia, . Article in Press. 

Mashour, G.A.^a , Ben Abdallah, A.^b , Pryor, K.O.^c , El-Gabalawy, R.^{d e} , Vlisides, P.E.^a , Jacobsohn, E.^{f g} , Lenze, E.^h , Maybrier, H.R.^b , Veselis, R.A.^{c i} , Avidan, M.S.^b , PODCAST Research Group^j

^a Center for Consciousness Science, Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI, United States
^b Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, United States
^c Department of Anesthesiology, Weill Cornell Medicine, New York, NY, United States
^d Department of Clinical Health Psychology, University of Manitoba, Winnipeg, MB, Canada
^e Department of Anesthesia and Perioperative Medicine, University of Manitoba, Winnipeg, MB, Canada
^f Department of Anesthesia, University of Manitoba, Winnipeg, MB, Canada
^g Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada
^h Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
ⁱ Department of Neuroanesthesiology, Memorial Sloan Kettering Cancer Center, New York, NY, United States

Abstract
Background: Ketamine is a general anaesthetic with anti-depressant effects at subanaesthetic doses. We hypothesised that intraoperative administration of ketamine would prevent or mitigate postoperative depressive symptoms in surgical patients. Methods: We conducted an international, randomised clinical trial testing the effects of intraoperative administration of ketamine [0.5 mg kg−1 (Lo-K) or 1.0 mg kg−1 (Hi-K)] vs control [saline placebo (P)] in patients ≥60 yr old undergoing major surgery with general anaesthesia. We administered the Patient Health Questionnaire-8 before the operation, on postoperative day (POD) 3 (primary outcome), and on POD30 to assess depressive symptoms, a secondary outcome of the original trial. Results: There was no significant difference on POD3 in the proportion of patients with symptoms suggestive of depression between the placebo [23/156 (14.7%)] and combined ketamine (Lo-K plus Hi-K) [61/349 (17.5%)] groups [difference = –2.7%; 95% confidence interval (CI), 5.0% to –9.4%; P=0.446]. Of the total cohort, 9.6% (64/670; 95% CI, 7.6–12.0%) had symptoms suggestive of depression before operation, which increased to 16.6% (84/505; 95% CI, 13.6–20.1%) on POD3, and decreased to 11.9% (47/395; 95% CI, 9.1–15.5%) on POD30. Of the patients with depressive symptoms on POD3 and POD30, 51% and 49%, respectively, had no prior history of depression or depressive symptoms. Conclusions: Major surgery is associated with new-onset symptoms suggestive of depression in patients ≥60 yr old. Intraoperative administration of subanaesthetic ketamine does not appear to prevent or improve depressive symptoms. Clinical trials registration: NCT01690988. © 2018 British Journal of Anaesthesia

Author Keywords
anti-depressant;  depression;  ketamine;  surgery

Document Type: Article in Press
Source: Scopus

A novel cognitive disease progression model for clinical trials in autosomal-dominant Alzheimer’s disease
(2018) Statistics in Medicine, . Article in Press. 

Wang, G.^a , Berry, S.^b , Xiong, C.^a , Hassenstab, J.^c , Quintana, M.^b , Mcdade, E.M.^c , Delmar, P.^d , Vestrucci, M.^{d e} , Sethuraman, G.^f , Bateman, R.J.^c

^a Division of Biostatistics Washington University School of Medicine St. Louis, MO USA
^b Berry Consultants Austin, TX USA
^c Department of Neurology Washington University School of Medicine St. Louis, MO USA
^d F. Hoffmann-La Roche Ltd. Basel Switzerland
^e Department of Statistics and Data Sciences University of Texas at Austin Austin, TX USA
^f Lilly Research Laboratories Indianapolis, IN USA

Abstract
Clinical trial outcomes for Alzheimer’s disease are typically analyzed by using the mixed model for repeated measures (MMRM) or similar models that compare an efficacy scale change from baseline between treatment arms with or without participants’ disease stage as a covariate. The MMRM focuses on a single-point fixed follow-up duration regardless of the exposure for each participant. In contrast to these typical models, we have developed a novel semiparametric cognitive disease progression model (DPM) for autosomal dominant Alzheimer’s disease based on the Dominantly Inherited Alzheimer Network (DIAN) observational study. This model includes 3 novel features, in which the DPM (1) aligns and compares participants by disease stage, (2) uses a proportional treatment effect similar to the concept of the Cox proportional hazard ratio, and (3) incorporates extended follow-up data from participants with different follow-up durations using all data until last participant visit. We present the DPM model developed by using the DIAN observational study data and demonstrate through simulation that the cognitive DPM used in hypothetical intervention clinical trials produces substantial gains in power compared with the MMRM. © 2018 John Wiley & Sons, Ltd.

Author Keywords
Alzheimer’s disease;  Disease progression model;  Mixed effects model for repeated measures;  Proportional treatment effect

Document Type: Article in Press
Source: Scopus

Intermittent Fasting Confers Protection in CNS Autoimmunity by Altering the Gut Microbiota
(2018) Cell Metabolism, . Article in Press. 

Cignarella, F.^a , Cantoni, C.^a , Ghezzi, L.^{a b} , Salter, A.^c , Dorsett, Y.^d , Chen, L.^d , Phillips, D.^d , Weinstock, G.M.^d , Fontana, L.^{e f g} , Cross, A.H.^{a h} , Zhou, Y.^{d i} , Piccio, L.^{a h}

^a Department of Neurology, Washington University School of Medicine, Campus Box 8111, 660 S. Euclid Avenue, St. Louis, MO, United States
^b Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Milan, Italy
^c Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
^d Jackson Laboratory for Genomic Medicine, Farmington, CT, United States
^e Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Clinical and Experimental Sciences, Brescia University Medical School, Brescia, Italy
^g CEINGE Biotecnologie Avanzate, Napoli, Italy
^h Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO, United States
ⁱ Department of Medicine and OB/GYN, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT, United States

Abstract
Multiple sclerosis (MS) is more common in western countries with diet being a potential contributing factor. Here we show that intermittent fasting (IF) ameliorated clinical course and pathology of the MS model, experimental autoimmune encephalomyelitis (EAE). IF led to increased gut bacteria richness, enrichment of the Lactobacillaceae, Bacteroidaceae, and Prevotellaceae families and enhanced antioxidative microbial metabolic pathways. IF altered T cells in the gut with a reduction of IL-17 producing T cells and an increase in regulatory T cells. Fecal microbiome transplantation from mice on IF ameliorated EAE in immunized recipient mice on a normal diet, suggesting that IF effects are at least partially mediated by the gut flora. In a pilot clinical trial in MS patients, intermittent energy restriction altered blood adipokines and the gut flora resembling protective changes observed in mice. In conclusion, IF has potent immunomodulatory effects that are at least partially mediated by the gut microbiome. Intermittent fasting confers protection in the multiple sclerosis animal model through effects on the gut microbiota; similar changes to the gut microbiota were observed in relapsing multiple sclerosis patients undergoing intermittent energy restriction. © 2018 Elsevier Inc.

Author Keywords
diet;  experimental autoimmune encephalomyelitis;  gut microbiota;  intermittent fasting;  multiple sclerosis

Document Type: Article in Press
Source: Scopus

Recurrent information optimization with local, metaplastic synaptic dynamics
(2017) Neural Computation, 29 (9), pp. 2528-2552. 

Liu, S., Ching, S.

Department of Electrical and Systems Engineering, Washington University, St. Louis, MO, United States

Abstract
We consider the problem of optimizing information-theoretic quantities in recurrent networks via synaptic learning. In contrast to feedforward networks, the recurrence presents a key challenge insofar as an optimal learning rule must aggregate the joint distribution of the whole network. This challenge, in particular, makes a local policy (i.e., one that depends on only pairwise interactions) difficult. Here, we report a local metaplastic learning rule that performs approximate optimization by estimating whole-network statistics through the use of several slow, nested dynamical variables. These dynamics provide the rule with both anti-Hebbian and Hebbian components, thus allowing for decorrelating and correlating learning regimes that can occur when either is favorable for optimality. We demonstrate the performance of the synthesized rule in comparison to classical BCM dynamics and use the networks to conduct history-dependent tasks that highlight the advantages of recurrence. Finally, we show the consistency of the resultant learned networks with notions of criticality, including balanced ratios of excitation and inhibition. © 2017 Massachusetts Institute of Technology.

Document Type: Letter
Source: Scopus