WashU weekly Neuroscience publications | Office of Neuroscience Research

"Sex-specific glioma genome-wide association study identifies new risk locus at 3p21.31 in females, and finds sex-differences in risk at 8q24.21" (2018) Scientific Reports

Sex-specific glioma genome-wide association study identifies new risk locus at 3p21.31 in females, and finds sex-differences in risk at 8q24.21
(2018) Scientific Reports, 8 (1), art. no. 7352, .

Ostrom, Q.T.^a ^b ^c , Kinnersley, B.^d , Wrensch, M.R.^e , Eckel-Passow, J.E.^f , Armstrong, G.^a , Rice, T.^e , Chen, Y.^b , Wiencke, J.K.^e , McCoy, L.S.^e , Hansen, H.M.^e , Amos, C.I.^g , Bernstein, J.L.^h , Claus, E.B.ⁱ ^j , Il’yasova, D.^k ^l ^m , Johansen, C.ⁿ ^o , Lachance, D.H.^p , Lai, R.K.^q ^r , Merrell, R.T.^s , Olson, S.H.^h , Sadetzki, S.^t ^u , Schildkraut, J.M.^v , Shete, S.^w , Rubin, J.B.^x ^y , Lathia, J.D.^z , Berens, M.E.^aa , Andersson, U.^ab , Rajaraman, P.^ac , Chanock, S.J.^ac ^ad , Linet, M.S.^ac , Wang, Z.^ac ^ad , Yeager, M.^ac ^ad , Beane Freeman, L.E.^ac , Koutros, S.^ac , Albanes, D.^ac , Visvanathan, K.^af , Stevens, V.L.^ag , Henriksson, R.^ah , Michaud, D.S.^ai , Feychting, M.^aj , Ahlbom, A.^aj , Giles, G.G.^ak , Milne, R.^ak , McKean-Cowdin, R.^r , Le Marchand, L.^al , Stampfer, M.^am ^an , Ruder, A.M.^ao , Carreon, T.^ap , Hallmans, G.^aq , Zeleniuch-Jacquotte, A.^ar , Gaziano, J.M.^as , Sesso, H.D.^am , Purdue, M.P.^ac , White, E.^at , Peters, U.^at , Buring, J.^am , Houlston, R.S.^d , Jenkins, R.B.^ae , Melin, B.^ab , Bondy, M.L.^a , Barnholtz-Sloan, J.S.^b

^a Department of Medicine, Baylor College of Medicine, Houston, TX, United States
^b Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, OH, United States
^c Department of Population and Quantitative Heath Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, United States
^d Institute of Cancer Research, Division of Genetics and Epidemiology, Sutton, Surrey, United Kingdom
^e Department of Neurological Surgery and Institute of Human Genetics, School of Medicine, University of California San Francisco, San Francisco, CA, United States
^f Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN, United States
^g Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, United States
^h Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, United States
ⁱ School of Public Health, Yale University, New Haven, CT, United States
^j Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA, United States
^k Department of Epidemiology and Biostatistics, School of Public Health, Georgia State University, Atlanta, United States
^l Cancer Control and Prevention Program, Duke University Medical Center, Durham, NC, United States
^m Duke University Medical Center, Duke Cancer Institute, Durham, NC, United States
ⁿ Finsen Center, Oncology clinic, Rigshospitalet, Copenhagen, Denmark
^o Survivorship Research Unit, Copenhagen, Denmark
^p Department of Neurology, Mayo Clinic Comprehensive Cancer Center, Rochester, MN, United States
^q Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
^r Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
^s Department of Neurology, NorthShore University HealthSystem, Evanston, il, United States
^t Chaim Sheba Medical Center, Cancer and Radiation Epidemiology Unit, Gertner Institute, Tel Hashomer, Israel
^u Department of Epidemiology and Preventive Medicine, School of Public Health, Tel-Aviv University, Tel-Aviv, Israel
^v Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, United States
^w Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, United States
^x Department of Pediatrics, School of Medicine, Washington University, St. Louis, MO, United States
^y Department of Neuroscience, School of Medicine, Washington University, St. Louis, MO, United States
^z Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Foundation, Cleveland, OH, United States
^aa Translational Genomics Research Institute, Cancer and Cell Biology Division, Phoenix, AZ, United States
^ab Department of Radiation Sciences, Faculty of Medicine, Umea University, Umea, Sweden
^ac Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, United States
^ad National Cancer Institute, Core Genotyping Facility, SAIC-Frederick, Inc, Gaithersburg, MD, United States
^ae Department of Laboratory Medicine and Pathology, Mayo Clinic Comprehensive Cancer Center, Rochester, MN, United States
^af Department of Epidemiology, United States of America, John Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
^ag American Cancer Society, Atlanta, GA, United States
^ah Department of Oncology, Karolinska University Hospital, Stockholm, Sweden
^ai Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, MA, United States
^aj Institute of Environmental Medicine, Stockholm, Sweden
^ak Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, Australia
^al Department of Public Health, John A. Burns School of Medicine, University of Hawaii at Manoa, Manoma, HI, United States
^am Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, United States
^an Department of Epidemiology Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, United States
^ao Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Atlanta, GA, United States
^ap Division of Surveillance and Field Studies, Hazard Evaluations, Atlanta, GA, United States
^aq Department of Public Health and Clinical Medicine, Faculty of Medicine, Umea University, Umea, Sweden
^ar Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, NY, United States
^as Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
^at Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, Seattle, WA, United States

Abstract
Incidence of glioma is approximately 50% higher in males. Previous analyses have examined exposures related to sex hormones in women as potential protective factors for these tumors, with inconsistent results. Previous glioma genome-wide association studies (GWAS) have not stratified by sex. Potential sex-specific genetic effects were assessed in autosomal SNPs and sex chromosome variants for all glioma, GBM and non-GBM patients using data from four previous glioma GWAS. Datasets were analyzed using sex-stratified logistic regression models and combined using meta-analysis. There were 4,831 male cases, 5,216 male controls, 3,206 female cases and 5,470 female controls. A significant association was detected at rs11979158 (7p11.2) in males only. Association at rs55705857 (8q24.21) was stronger in females than in males. A large region on 3p21.31 was identified with significant association in females only. The identified differences in effect of risk variants do not fully explain the observed incidence difference in glioma by sex. © 2018 The Author(s).

Document Type: Article
Source: Scopus

"ModCHIMERA: A novel murine closed-head model of moderate traumatic brain injury" (2018) Scientific Reports

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

"Local functional connectivity alterations in schizophrenia, bipolar disorder, and major depressive disorder" (2018) Journal of Affective Disorders

Local functional connectivity alterations in schizophrenia, bipolar disorder, and major depressive disorder
(2018) Journal of Affective Disorders, 236, pp. 266-273.

Wei, Y.^a ^b , Chang, M.^b ^c , Womer, F.Y.^d , Zhou, Q.^a ^b , Yin, Z.^a ^b , Wei, S.^b ^c , Zhou, Y.^a ^b ^e , Jiang, X.^b ^c , Yao, X.^a ^b , Duan, J.^a ^b , Xu, K.^c , Zuo, X.-N.^f , Tang, Y.^a ^b ^e , Wang, F.^a ^b ^c

^a Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
^b Brain Function Research Section, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
^c Department of Radiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
^d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
^f CAS Key Laboratory of Behavioral Science, Institute of Psychology, Beijing, China

Abstract
Background: Local functional connectivity (FC) indicates local or short-distance functional interactions and may serve as a neuroimaging marker to investigate the human brain connectome. Local FC alterations suggest a disrupted balance in the local functionality of the whole brain network and are increasingly implicated in schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD). Methods: We aim to examine the similarities and differences in the local FC across SZ, BD, and MDD. In total, 537 participants (SZ, 126; BD, 97; MDD, 126; and healthy controls, 188) completed resting-state functional magnetic resonance imaging at a single site. The local FC at resting state was calculated and compared across SZ, BD, and MDD. Results: The local FC increased across SZ, BD, and MDD within the bilateral orbital frontal cortex (OFC) and additional region in the left OFC extending to putamen and decreased in the primary visual, auditory, and motor cortices, right supplemental motor area, and bilateral thalami. There was a gradient in the extent of alterations such that SZ > BD > MDD. Limitations: This cross-sectional study cannot consider medications and other clinical variables. Conclusions: These findings indicate a disrupted balance between network integration and segregation in SZ, BD, and MDD, including over-integration via increased local FC in the OFC and diminished segregation of neural processing with the weakening of the local FC in the primary sensory cortices and thalamus. The shared local FC abnormalities across SZ, BD, and MDD may shed new light on the potential biological mechanisms underlying these disorders. © 2018 Elsevier B.V.

Document Type: Article
Source: Scopus

"Internode length is reduced during myelination and remyelination by neurofilament medium phosphorylation in motor axons" (2018) Experimental Neurology

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

"Long term electroencephalography in preterm neonates: Safety and quality of electrode types" (2018) Clinical Neurophysiology

Long term electroencephalography in preterm neonates: Safety and quality of electrode types
(2018) Clinical Neurophysiology, 129 (7), pp. 1366-1371.

El Ters, N.M.^a , Mathur, A.M.^a , Jain, S.^b , Vesoulis, Z.A.^a , Zempel, J.M.^b

^a Division of Newborn Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^b Division of Pediatric Neurology, Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Objectives: The objective of this study was to compare gold cup and hydrogel electrodes for frequency of electrode replacement, longevity of the original electrodes after initial placement, recording quality, and skin safety issues in long-term EEG studies in preterm neonates. Methods: We performed a prospective trial with newborns born at ≥23 weeks and ≤30 weeks of gestational age (GA). Two mirror image EEG electrode arrays were utilized on consecutive subjects, where gold cup electrodes alternated with hydrogel electrodes. Results: Our sample included 50 neonates with mean GA of 27 (±1) weeks. The mean recording time was 84 (±15) hours. No difference was present in the frequency of replacement of either type across the total recording time (p = 0.8). We collected the time at which electrodes were first replaced, and found that hydrogel electrodes showed a longer uninterrupted recording time of 28(±2) hours vs. 20(±2) hours for gold cup electrodes (p = 0.01). Recording quality was similar in either type (p = 0.2). None of the patients experienced significant skin irritation from a discrete electrode. Conclusion: Long-term EEG studies can be performed with either gold cup or hydrogel electrodes, validating the safety and quality of both electrode types. Significance: Hydrogel electrodes are a reasonable alternative for use in long-term EEG studies in preterm neonates. © 2018 International Federation of Clinical Neurophysiology

Author Keywords
Electrode; Electroencephalography; Gold cup; Hydrogel; Quality; Safety

Document Type: Article
Source: Scopus

"TDP-43 interacts with mitochondrial proteins critical for mitophagy and mitochondrial dynamics" (2018) Neuroscience Letters

TDP-43 interacts with mitochondrial proteins critical for mitophagy and mitochondrial dynamics
(2018) Neuroscience Letters, 678, pp. 8-15.

Davis, S.A.^a ^b , Itaman, S.^a , Khalid-Janney, C.M.^a , Sherard, J.A.^a , Dowell, J.A.^c , Cairns, N.J.^d , Gitcho, M.A.^a ^b

^a Department of Biological Sciences, Delaware State University, Dover, DE, United States
^b Delaware Center for Neuroscience Research, Delaware State University, Dover, DE, United States
^c Wisconsin Institutes for Discovery, Madison, WI, United States
^d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Transactive response DNA-binding protein of 43 kDa (TDP-43) functions as a heterogeneous nuclear ribonucleoprotein and is the major pathological protein in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). TDP-43 pathology may also be present as a comorbidity in approximately 20–50% of sporadic Alzheimer’s disease cases. In a mouse model of MND, full-length TDP-43 increases association with the mitochondria and blocking the TDP-43/mitochondria interaction ameliorates motor dysfunction. Utilizing a proteomics screen, several mitochondrial TDP-43-interacting partners were identified, including voltage-gated anion channel 1 (VDAC1) and prohibitin 2 (PHB2), a crucial mitophagy receptor. Overexpression of TDP-43 led to an increase in PHB2 whereas TDP-43 knockdown reduced PHB2 expression in cells treated with carbonyl cyanide m-chlorophenylhydrazone (CCCP), an inducer of mitophagy. These results suggest that TDP-43 expression contributes to metabolism and mitochondrial function however we show no change in bioenergetics when TDP-43 is overexpressed and knocked down in HEK293T cells. Furthermore, the fusion protein mitofusin 2 (MFN2) interacts in complex with TDP-43 and selective expression of human TDP-43 in the hippocampus and cortex induced an age-dependent change in Mfn2 expression. Mitochondria morphology is altered in 9-month-old mice selectively expressing TDP-43 in an APP/PS1 background compared with APP/PS1 littermates. We further confirmed TDP-43 localization to the mitochondria using immunogold labeled TDP-43 transmission electron microscopy (TEM) and mitochondrial isolation methods There was no increase in full-length TDP-43 localized to the mitochondria in APP/PS1 mice compared to wild-type (littermates); however, using C- and N-terminal-specific TDP-43 antibodies, the N-terminal (27 kDa, N27) and C-terminal (30 kDa, C30) fragments of TDP-43 are greatly enriched in mitochondrial fractions. In addition, when the mitochondrial peptidase (PMPCA) is overexpressed there is an increase in the N-terminal fragment (N27). These results suggest that TDP-43 processing may contribute to metabolism and mitochondrial function. © 2018 The Authors

Author Keywords
APP/PS1; MFN2; Mitochondria; Mitophagy; PHB2; PMPCA; TDP-43

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

"Readmission after spinal cord injury: Analysis of an institutional cohort of 795 patients" (2018) Journal of Neurosurgical Sciences

Readmission after spinal cord injury: Analysis of an institutional cohort of 795 patients
(2018) Journal of Neurosurgical Sciences, 62 (3), pp. 265-270.

Yarbrough, C.K.^a , Gamble, P.G.^b , Burhan Janjua, M.^c , Tang, M.^b , Ghenbot, R.^b , Zhang, A.J.^d , Juknis, N.^e , Hawasli, A.H.^a , Kelly, M.P.^f , Ray, W.Z.^a

^a Department of Neurological Surgery, Washington University School of Medicine, 60 S. Euclid Avenue, Campus Box 8057, St. Louis, MO, United States
^b Washington University School of Medicine, St. Louis, MO, United States
^c Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States
^d University of Minnesota School of Medicine, Minneapolis, MN, United States
^e Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO, United States

Abstract
BACKGROUND: Recent studies in other fields have suggested that healthcare on the weekend may have worse outcomes. In particular, patients with stroke and acute cardiovascular events have shown worse outcomes with weekend treatment. It is unclear whether this extends to patients with spinal cord injury. This study was designed to evaluate factors for readmission after index hospitalization for spinal cord injury. METHODS: A total of 795 consecutive patients over an 11-year period were analyzed. After excluding patients with chronic spinal cord injury and surgical care at an outside hospital, 745 patients remained. The primary outcome measure evaluated was 30-day readmission. Secondary measures include perioperative complications, readmission rate when discharged on the weekend, and the effect of race and insurance status on readmission rate. Univariate and multivariate analysis were utilized to evaluate the covariates collected. The χ2 test, Fisher’s exact test, and linear and logistic regression methods were utilized for statistical analysis. RESULTS: A total of 745 patients were analyzed after exclusions. Payer status did not affect length of stay, ICU length of stay, or perioperative complications. Neither weekend admission nor weekend operation affected length of stay, ICU length of stay, or readmission by 30 days. Patients undergoing weekend surgical treatment had lower perioperative complication rates (2.2% vs. 6.5% on weekday, P<0.01). Discharge on the weekend was associated with a significantly lower rate of readmission by 30 days (OR=0.07, 95% CI: 0.009-0.525, P<0.005). Payer status was associated with 30-day readmission (P<0.005). Patients with Medicare (20.8%) and Medicaid (20.1%) showed higher rates of readmission than patients with other payers. 21.1% of African-American patients were readmitted, versus 10.2% of other patients (Odds ratio: 2.2, 95% confidence interval 1.36-3.27, P<0.001). Correcting for payer status lessened but did not eliminate the effect of race on readmission. CONCLUSIONS: Weekend admission did not increase perioperative complications or hospital length of stay. After discharge, patients with Medicaid and Medicare show higher rates of 30-day readmission, as do African-American patients. The effect of race on readmission is multifactorial, and may partially explained by the increased rate of Medicaid coverage in African-Americans in our institutions catchment area. © 2018 Edizioni Minerva Medica.

Author Keywords
Critical care; Healthcare disparities; Nervous system trauma; Neurosurgical procedure; Spinal cord injury; Spinal fusion

Document Type: Article
Source: Scopus

"Pre-clinical MR elastography: principles, techniques, and applications" (2018) Journal of Magnetic Resonance

Pre-clinical MR elastography: principles, techniques, and applications
(2018) Journal of Magnetic Resonance, 291, pp. 73-83.

Bayly, P.V.^a , Garbow, J.R.^b

^a Mechanical Engineering and Materials Science, Washington University in Saint LouisMissouri, United States
^b Radiology, Washington University School of Medicine, Saint Louis, Missouri, United States

Abstract
Magnetic resonance elastography (MRE) is a method for measuring the mechanical properties of soft tissue in vivo, non-invasively, by imaging propagating shear waves in the tissue. The speed and attenuation of waves depends on the elastic and dissipative properties of the underlying material. Tissue mechanical properties are essential for biomechanical models and simulations, and may serve as markers of disease, injury, development, or recovery. MRE is already established as a clinical technique for detecting and characterizing liver disease. The potential of MRE for diagnosing or characterizing disease in other organs, including brain, breast, and heart is an active research area. Studies involving MRE in the pre-clinical setting, in phantoms and artificial biomaterials, in the mouse, and in other mammals, are critical to the development of MRE as a robust, reliable, and useful modality. © 2018

Document Type: Article
Source: Scopus

"Viruses have multiple paths to central nervous system pathology" (2018) Current Opinion in Neurology

Viruses have multiple paths to central nervous system pathology
(2018) Current Opinion in Neurology, 31 (3), pp. 313-317.

Agner, S.C.^a , Klein, R.S.^b ^c ^d

^a Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
^b Department of Medicine, Washington University, School of Medicine, St. Louis, MO, United States
^c Department of Pathology and Immunology, Washington University, School of Medicine, St. Louis, MO, United States
^d Department of Neuroscience, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
Purpose of review Although viral infections of the central nervous system (CNS) are known to acutely cause pathology in the form of cytokine-mediated neural tissue damage and inflammation, the pathophysiology of neurologic sequelae after viral clearance is incompletely understood. Recent findings Alterations in microglial and glial biology in response to initial infiltration of immune cells that persist within the CNS have recently been shown to promote neuronal dysfunction and cognitive deficits in animal models of viral encephalitis. Summary The current review summarizes the current knowledge on the possible role of innate immune signaling during acute infections as triggers of neurologic sequelae that persist, and may even worsen, after clearance of viral infections within the CNS. © Copyright 2018 Wolters Kluwer Health, Inc. All rights reserved.

Author Keywords
encephalomyelitis; Guillain-Barré syndrome; HIV-associated neurocognitive disorder; microcephaly

Document Type: Review
Source: Scopus

"Recommendations and Extraction of Clinical Variables of Pediatric Multiple Sclerosis Using Common Data Elements" (2018) Journal of Neuroscience Nursing

Recommendations and Extraction of Clinical Variables of Pediatric Multiple Sclerosis Using Common Data Elements
(2018) Journal of Neuroscience Nursing, 50 (3), pp. 171-176.

Newland, P.^a , Newland, J.M.^b , Hendricks-Ferguson, V.L.^c , Smith, J.M.^a , Oliver, B.J.^d ^e ^f

^a Goldfarb School of Nursing, Barnes Jewish College, St. Louis, MO, United States
^b Washington University in St. Louis, St. Louis, MO, United States
^c St. Louis University School of Nursing, St. Louis, MO, United States
^d Dartmouth Institute, Geisel School of Medicine, United States
^e School of Nursing, MGH Institute of Health Professions, Boston, MA, United States
^f White River Junction, VT, United States

Abstract
Purpose: The purpose of this article was to demonstrate the feasibility of using common data elements (CDEs) to search for information on the pediatric patient with multiple sclerosis (MS) and provide recommendations for future quality improvement and research in the use of CDEs for pediatric MS symptom management strategies Methods: The St. Louis Children’s Hospital (SLCH), Washington University (WU) pediatrics data network was evaluated for use of CDEs identified from a database to identify variables in pediatric MS, including the key clinical features from the disease course of MS. The algorithms used were based on International Classification of Diseases, Ninth/Tenth Revision, codes and text keywords to identify pediatric patients with MS from a de-identified database. Data from a coordinating center of SLCH/WU pediatrics data network, which houses inpatient and outpatient records consisting of patients (N = 498 000), were identified, and detailed information regarding the clinical course of MS were located from the text of the medical records, including medications, presence of oligoclonal bands, year of diagnosis, and diagnosis code. Results: There were 466 pediatric patients with MS, with a few also having the comorbid diagnosis of anxiety and depression. Conclusions: St. Louis Children’s Hospital/WU pediatrics data network is one of the largest databases in the United States of detailed data, with the ability to query and validate clinical data for research on MS. Nurses and other healthcare professionals working with pediatric MS patients will benefit from having common disease identifiers for quality improvement, research, and practice. The increased knowledge of big data from SLCH/WU pediatrics data network has the potential to provide information for intervention and decision-making that can be personalized to the pediatric MS patient. © 2018 American Association of Neuroscience Nurses.

Author Keywords
common data elements (CDEs); evidence based practice; pediatric multiple sclerosis

Document Type: Article
Source: Scopus

"The Microglial Innate Immune Receptor TREM2 Is Required for Synapse Elimination and Normal Brain Connectivity" (2018) Immunity

The Microglial Innate Immune Receptor TREM2 Is Required for Synapse Elimination and Normal Brain Connectivity
(2018) Immunity, 48 (5), pp. 979-991.e8. Cited 1 time.

Filipello, F.^a ^j , Morini, R.^b , Corradini, I.^b ^c , Zerbi, V.^d , Canzi, A.^a , Michalski, B.^e , Erreni, M.^f , Markicevic, M.^d , Starvaggi-Cucuzza, C.^b , Otero, K.^g , Piccio, L.^h , Cignarella, F.^h , Perrucci, F.^b , Tamborini, M.^b , Genua, M.^f , Rajendran, L.ⁱ , Menna, E.^b ^c , Vetrano, S.^a , Fahnestock, M.^e , Paolicelli, R.C.ⁱ , Matteoli, M.^b ^c

^a Humanitas University, Department of Biomedical Sciences, Via Rita Levi Montalcini, Pieve Emanuele – Milan, Italy
^b Laboratory of Pharmacology and Brain Pathology, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano – Milan, Italy
^c IN-CNR, Milano, Italy
^d Neural Control of Movement Lab, HEST, ETH Zürich, Winterthurerstrasse 190, Zurich, Switzerland
^e Department of Psychiatry & Behavioural Neurosciences, HSC-4N80, McMaster University, Hamilton, ON, Canada
^f Department of Immunology and Inflammation, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano – Milan, Italy
^g Department of Neuroimmunology, Acute Neurology and Pain, Biogen Inc., 115 Broadway, Cambridge, MA, United States
^h Department of Neurology, Washington University, St. Louis, MO, United States
ⁱ Systems and Cell Biology of Neurodegeneration, IREM, University of Zurich, Schlieren, Switzerland
^j Department of Neurology, Washington University, St. LouisMO, United States

Abstract
The triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial innate immune receptor associated with a lethal form of early, progressive dementia, Nasu-Hakola disease, and with an increased risk of Alzheimer’s disease. Microglial defects in phagocytosis of toxic aggregates or apoptotic membranes were proposed to be at the origin of the pathological processes in the presence of Trem2 inactivating mutations. Here, we show that TREM2 is essential for microglia-mediated synaptic refinement during the early stages of brain development. The absence of Trem2 resulted in impaired synapse elimination, accompanied by enhanced excitatory neurotransmission and reduced long-range functional connectivity. Trem2−/− mice displayed repetitive behavior and altered sociability. TREM2 protein levels were also negatively correlated with the severity of symptoms in humans affected by autism. These data unveil the role of TREM2 in neuronal circuit sculpting and provide the evidence for the receptor’s involvement in neurodevelopmental diseases. TREM2 is a microglial innate immune receptor whose functions during brain development are still unknown. Filipello et al. demonstrate that TREM2 is essential for microglia to eliminate supernumerary synapses in the developing brain. TREM2 protein was also reduced in autistic patients, suggesting that the receptor may be involved in neurodevelopmental diseases. © 2018 Elsevier Inc.

Author Keywords
autism; development; microglia; PSD95; synapse; synaptic pruning; TREM2

Document Type: Article
Source: Scopus

"AMPA-ergic regulation of amyloid-β levels in an Alzheimer's disease mouse model" (2018) Molecular Neurodegeneration

AMPA-ergic regulation of amyloid-β levels in an Alzheimer’s disease mouse model
(2018) Molecular Neurodegeneration, 13 (1), art. no. 22, .

Hettinger, J.C.^a , Lee, H.^a , Bu, G.^b , Holtzman, D.M.^a , Cirrito, J.R.^a

^a Department of Neurology, Knight Alzheimer’s Disease Research Center, Hope Center for Neurological Disorders, Washington University, School of Medicine, Campus Box 8111, 660 South Euclid Avenue, St. Louis, MO, United States
^b Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States

Abstract
Background: Extracellular aggregation of the amyloid-β (Aβ) peptide into toxic multimers is a key event in Alzheimer’s disease (AD) pathogenesis. Aβ aggregation is concentration-dependent, with higher concentrations of Aβ much more likely to form toxic species. The processes that regulate extracellular levels of Aβ therefore stand to directly affect AD pathology onset. Studies from our lab and others have demonstrated that synaptic activity is a critical regulator of Aβ production through both presynaptic and postsynaptic mechanisms. AMPA receptors (AMPA-Rs), as the most abundant ionotropic glutamate receptors, have the potential to greatly impact Aβ levels. Methods: In order to study the role of AMPA-Rs in Aβ regulation, we used in vivo microdialysis in an APP/PS1 mouse model to simultaneously deliver AMPA and other treatments while collecting Aβ from the interstitial fluid (ISF). Changes in Aβ production and clearance along with inflammation were assessed using biochemical approaches. IL-6 deficient mice were utilized to test the role of IL-6 signaling in AMPA-R-mediated regulation of Aβ levels. Results: We found that AMPA-R activation decreases in ISF Aβ levels in a dose-dependent manner. Moreover, the effect of AMPA treatment involves three distinct pathways. Steady-state activity of AMPA-Rs normally promotes higher ISF Aβ. Evoked AMPA-R activity, however, decreases Aβ levels by both stimulating glutamatergic transmission and activating downstream NMDA receptor (NMDA-R) signaling and, with extended AMPA treatment, acting independently of NMDA-Rs. Surprisingly, we found this latter, direct AMPA pathway of Aβ regulation increases Aβ clearance, while Aβ production appears to be largely unaffected. Furthermore, the AMPA-dependent decrease is not observed in IL-6 deficient mice, indicating a role for IL-6 signaling in AMPA-R-mediated Aβ clearance. Conclusion: Though basal levels of AMPA-R activity promote higher levels of ISF Aβ, evoked AMPA-R signaling decreases Aβ through both NMDA-R-dependent and -independent pathways. We find that evoked AMPA-R signaling increases clearance of extracellular Aβ, at least in part through enhanced IL-6 signaling. These data emphasize that Aβ regulation by synaptic activity involves a number of independent pathways that together determine extracellular Aβ levels. Understanding how these pathways maintain Aβ levels prior to AD pathology may provide insights into disease pathogenesis. © 2018 The Author(s).

Author Keywords
Alzheimer’s disease; AMPA; Amyloid-beta; Clearance; IL-6; Microdialysis

Document Type: Article
Source: Scopus

"Cognitive and neurophysiological recovery following electroconvulsive therapy: A study protocol" (2018) Frontiers in Psychiatry

Cognitive and neurophysiological recovery following electroconvulsive therapy: A study protocol
(2018) Frontiers in Psychiatry, 9 (MAY), art. no. 171, .

Palanca, B.J.A.^a ^b , Maybrier, H.R.^a , Mickle, A.M.^a , Farber, N.B.^c , Hogan, R.E.^d , Trammel, E.R.^a , Spencer, J.W.^a , Bohnenkamp, D.D.^c , Wildes, T.S.^a , Ching, S.^b ^e , Lenze, E.^c , Basner, M.^f , Kelz, M.B.^g , Avidan, M.S.^a ^h

^a Department of Anesthesiology, Washington University School of Medicine in St. Louis, St Louis, MO, United States
^b Division of Biology and Biomedical Sciences, Washington University School of Medicine in St. Louis, St Louis, MO, United States
^c Department of Psychiatry, Washington University School of Medicine in St. Louis, St Louis, MO, United States
^d Department of Neurology, Washington University School of Medicine in St. Louis, St Louis, MO, United States
^e Department of Electrical Systems and Engineering, Washington University, St Louis, MO, United States
^f Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^g Department of Anesthesiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^h Department of Surgery, Washington University School of Medicine in St. Louis, St Louis, MO, United States

Abstract
Electroconvulsive therapy (ECT) employs the elective induction of generalizes seizures as a potent treatment for severe psychiatric illness. As such, ECT provides an opportunity to rigorously study the recovery of consciousness, reconstitution of cognition, and electroencephalographic (EEG) activity following seizures. Fifteen patients with major depressive disorder refractory to pharmacologic therapy will be enrolled (Clinicaltrials.gov, NCT02761330). Adequate seizure duration will be confirmed following right unilateral ECT under etomidate anesthesia. Patients will then undergo randomization for the order in which they will receive three sequential treatments: etomidate + ECT, ketamine + ECT, and ketamine + sham ECT. Sessions will be repeated in the same sequence for a total of six treatments. Before each session, sensorimotor speed, working memory, and executive function will be assessed through a standardized cognitive test battery. After each treatment, the return of purposeful responsiveness to verbal command will be determined. At this point, serial cognitive assessments will begin using the same standardized test battery. The presence of delirium and changes in depression severity will also be ascertained. Sixty-four channel EEG will be acquired throughout baseline, ictal, and postictal epochs. Mixed-effects models will correlate the trajectories of cognitive recovery, clinical outcomes, and EEG metrics over time. This innovative research design will answer whether: (1) time to return of responsiveness will be prolonged with ketamine + ECT compared with ketamine + sham ECT; (2) time of restoration to baseline function in each cognitive domain will take longer after ketamine + ECT than after ketamine + sham ECT; (3) postictal delirium is associated with delayed restoration of baseline function in all cognitive domains; and (4) the sequence of reconstitution of cognitive domains following the three treatments in this study is similar to that occurring after an isoflurane general anesthetic (NCT01911195). Sub-studies will assess the relationships of cognitive recovery to the EEG preceding, concurrent, and following individual ECT sessions. Overall, this study will lead the development of biomarkers for tailoring the cogno-affective recovery of patients undergoing ECT. © 2018 Palanca, Maybrier, Mickle, Farber, Hogan, Trammel, Spencer, Bohnenkamp, Wildes, Ching, Lenze, Basner, Kelz and Avidan.

Author Keywords
Anesthesia; Consciousness; Electroconvulsive therapy; Electroencephalography; Ketamine; Major depressive disorder; Neurocognitive disorders; Seizures

Document Type: Article
Source: Scopus

"Tracking the Influence of Autistic Traits on Competencies Among School Aged Children with Subthreshold Autistic Traits: A Longitudinal Study" (2018) Child Psychiatry and Human Development

Tracking the Influence of Autistic Traits on Competencies Among School Aged Children with Subthreshold Autistic Traits: A Longitudinal Study
(2018) Child Psychiatry and Human Development, pp. 1-15. Article in Press.

Crehan, E.T.^a ^d , Baer, J.^a , Althoff, R.R.^b , Constantino, J.N.^c

^a University of Vermont, 1 South Prospect, Burlington, VT, United States
^b University of Vermont, UHC Campus, 1 South Prospect, Box 364SJ 3m, Burlington, VT, United States
^c Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8504, St. Louis, MO, United States
^d Autism Assessment, Research, Treatment and Services (AARTS) Center, Rush University Medical Center, 1645 West Jackson Boulevard, Suite 603, Chicago, IL, United States

Abstract
This study aims to further explore the implications of autism spectrum disorder (ASD) symptoms for children who do not meet full diagnostic criteria. More specific characterization of how challenges present relative to traits of ASD such as social responsiveness is vital to developing an understanding of what competency and mental health difficulties these impairments are related to, and if they persist over time. Assessments of autistic traits, clinical symptomotology, and competency were used to quantify the relation of these domains cross-sectionally and across time. Social Responsiveness Scale (SRS) scores significantly contributed to a teacher-report Happy scale from the Teacher’s Report Form and a parent-report Social scale from the Child Behavior Checklist. No significant longitudinal models emerged. Splitting the SRS scores into three severity classes revealed that impaired social responsiveness is significantly related to competency, unlike average or below average deficits. Implications of subthreshold ASD traits on competency outcomes are discussed. © 2018 Springer Science+Business Media, LLC, part of Springer Nature

Author Keywords
Adaptive skills; ASD; Autism; Long-term outcomes; Subsyndromal traits

Document Type: Article in Press
Source: Scopus

"Tau seeding activity begins in the transentorhinal/entorhinal regions and anticipates phospho-tau pathology in Alzheimer’s disease and PART" (2018) Acta Neuropathologica

Tau seeding activity begins in the transentorhinal/entorhinal regions and anticipates phospho-tau pathology in Alzheimer’s disease and PART
(2018) Acta Neuropathologica, pp. 1-11. Article in Press.

Kaufman, S.K.^a ^b , Del Tredici, K.^c , Thomas, T.L.^a , Braak, H.^c , Diamond, M.I.^a

^a Center for Alzheimer’s and Neurodegenerative Diseases, NL10.120, Peter O’Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX, United States
^b Graduate Program in Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
^c Clinical Neuroanatomy Section/Department of Neurology, Center for Biomedical Research, University of Ulm, Ulm, Germany

Abstract
Alzheimer’s disease (AD) is characterized by accumulation of tau neurofibrillary tangles (NFTs) and, according to the prion model, transcellular propagation of pathological “seeds” may underlie its progression. Staging of NFT pathology with phospho-tau antibody is useful to classify AD and primary age-related tauopathy (PART) cases. The locus coeruleus (LC) shows the earliest phospho-tau signal, whereas other studies suggest that pathology begins in the transentorhinal/entorhinal cortices (TRE/EC). The relationship of tau seeding activity, phospho-tau pathology, and progression of neurodegeneration remains obscure. Consequently, we employed an established cellular biosensor assay to quantify tau seeding activity in fixed human tissue, in parallel with AT8 phospho-tau staining of immediately adjacent sections. We studied four brain regions from each of n = 247 individuals across a range of disease stages. We detected the earliest and most robust seeding activity in the TRE/EC. The LC did not uniformly exhibit seeding activity until later NFT stages. We also detected seeding activity in the superior temporal gyrus (STG) and primary visual cortex (VC) at stages before NFTs and/or AT8-immunopositivity were detectable. AD and putative PART cases exhibited similar patterns of seeding activity that anticipated histopathology across all NFT stages. Our findings are consistent with the prion model and suggest that pathological seeding activity begins in the TRE/EC rather than in the LC. In the analysis of tauopathy, quantification of seeding activity may offer an important addition to classical histopathology. © 2018 The Author(s)

Author Keywords
Alzheimer’s disease; FRET biosensor; Neurofibrillary tangles; Prion propagation; Tau seeding activity, Tau staging

Document Type: Article in Press
Source: Scopus

"A Programme for Risk Assessment and Minimisation of Progressive Multifocal Leukoencephalopathy Developed for Vedolizumab Clinical Trials" (2018) Drug Safety

A Programme for Risk Assessment and Minimisation of Progressive Multifocal Leukoencephalopathy Developed for Vedolizumab Clinical Trials
(2018) Drug Safety, pp. 1-10. Article in Press.

Parikh, A.^a , Stephens, K.^a ^h , Major, E.^b , Fox, I.^a , Milch, C.^a ⁱ , Sankoh, S.^a ^j , Lev, M.H.^c , Provenzale, J.M.^d , Shick, J.^e ^k , Patti, M.^a , McAuliffe, M.^a ^l , Berger, J.R.^f ^m , Clifford, D.B.^g

^a Takeda Pharmaceuticals International Co., 40 Landsdowne Street, Cambridge, MA, United States
^b National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
^c Massachusetts General Hospital, Boston, MA, United States
^d Duke University Medical Center, Durham, NC, United States
^e Takeda Pharmaceuticals International, Inc, Deerfield, IL, United States
^f University of Kentucky, Lexington, KY, United States
^g Washington University School of Medicine, St. Louis, MO, United States
^h Syros Pharmaceuticals, Cambridge, MA, United States
ⁱ Eli Lilly and Company, Indianapolis, IN, United States
^j Syndax Pharmaceuticals, Waltham, MA, United States
^k Gilead Sciences, Foster City, CA, United States
^l Biogen, Cambridge, MA, United States
^m University of Pennsylvania, Philadelphia, PA, United States

Abstract
Introduction: Over the past decade, the potential for drug-associated progressive multifocal leukoencephalopathy (PML) has become an increasingly important consideration in certain drug development programmes, particularly those of immunomodulatory biologics. Whether the risk of PML with an investigational agent is proven (e.g. extrapolated from relevant experience, such as a class effect) or merely theoretical, the serious consequences of acquiring PML require careful risk minimisation and assessment. No single standard for such risk minimisation exists. Vedolizumab is a recently developed monoclonal antibody to α4β7 integrin. Its clinical development necessitated a dedicated PML risk minimisation assessment as part of a global preapproval regulatory requirement. Objective: The aim of this study was to describe the multiple risk minimisation elements that were incorporated in vedolizumab clinical trials in inflammatory bowel disease patients as part of the risk assessment and minimisation of PML programme for vedolizumab. Methods: A case evaluation algorithm was developed for sequential screening and diagnostic evaluation of subjects who met criteria that indicated a clinical suspicion of PML. An Independent Adjudication Committee provided an independent, unbiased opinion regarding the likelihood of PML. Results: Although no cases were detected, all suspected PML events were thoroughly reviewed and successfully adjudicated, making it unlikely that cases were missed. Conclusion: We suggest that this programme could serve as a model for pragmatic screening for PML during the clinical development of new drugs. © 2018 The Author(s)

Document Type: Article in Press
Source: Scopus

"Coping with adversity: Individual differences in the perception of noisy and accented speech" (2018) Attention, Perception, and Psychophysics

Coping with adversity: Individual differences in the perception of noisy and accented speech
(2018) Attention, Perception, and Psychophysics, pp. 1-12. Article in Press.

McLaughlin, D.J.^a ^b , Baese-Berk, M.M.^a , Bent, T.^c , Borrie, S.A.^d , van Engen, K.J.^e

^a Department of Linguistics, University of Oregon, Eugene, OR, United States
^b Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Speech and Hearing Sciences, Indiana University, Bloomington, IN, United States
^d Department of Communicative Disorders and Deaf Education, Utah State University, Logan, UT, United States
^e Department of Psychological and Brain Sciences, Washington University, St. Louis, MO, United States

Abstract
During speech communication, both environmental noise and nonnative accents can create adverse conditions for the listener. Individuals recruit additional cognitive, linguistic, and/or perceptual resources when faced with such challenges. Furthermore, listeners vary in their ability to understand speech in adverse conditions. In the present study, we compared individuals’ receptive vocabulary, inhibition, rhythm perception, and working memory with transcription accuracy (i.e., intelligibility scores) for four adverse listening conditions: native speech in speech-shaped noise, native speech with a single-talker masker, nonnative-accented speech in quiet, and nonnative-accented speech in speech-shaped noise. The results showed that intelligibility scores for similar types of adverse listening conditions (i.e., with the same environmental noise or nonnative-accented speech) significantly correlated with one another. Furthermore, receptive vocabulary positively predicted performance globally across adverse listening conditions, and working memory positively predicted performance for the nonnative-accented speech conditions. Taken together, these results indicate that some cognitive resources may be recruited for all adverse listening conditions, while specific additional resources may be engaged when people are faced with certain types of listening challenges. © 2018 The Psychonomic Society, Inc.

Author Keywords
Inhibition; Speech perception; Working memory

Document Type: Article in Press
Source: Scopus

"Editorial: New advances in electrocochleography for clinical and basic investigation" (2018) Frontiers in Neuroscience

Editorial: New advances in electrocochleography for clinical and basic investigation
(2018) Frontiers in Neuroscience, 12 (MAY), art. no. 310, .

Pienkowski, M.^a , Adunka, O.F.^b , Lichtenhan, J.T.^c

^a Salus University, Elkins Park, PA, United States
^b Wexner Medical Center, The Ohio State University, Columbus, OH, United States
^c School of Medicine, Washington University in St. Louis, St. Louis, MO, United States

Author Keywords
Balance disorders; Cochlea; Cochlear implants; Electrocochleography (ECochG); Hearing disorders

Document Type: Editorial
Source: Scopus

"Anxiety in the orthopedic patient: using PROMIS to assess mental health" (2018) Quality of Life Research

Anxiety in the orthopedic patient: using PROMIS to assess mental health
(2018) Quality of Life Research, pp. 1-8. Article in Press.

Beleckas, C.M., Prather, H., Guattery, J., Wright, M., Kelly, M., Calfee, R.P.

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

Abstract
Purpose: This study explored the performance of the Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety assessment relative to the Depression assessment in orthopedic patients, the relationship between Anxiety with self-reported Physical Function and Pain Interference, and to determine if Anxiety levels varied according to the location of orthopedic conditions. Methods: This cross-sectional evaluation analyzed 14,962 consecutive adult new-patient visits to a tertiary orthopedic practice between 4/1/2016 and 12/31/2016. All patients completed PROMIS Anxiety, Depression, Physical Function, and Pain Interference computer adaptive tests (CATs) as routine clinical intake. Patients were grouped by the orthopedic service providing care and categorized as either affected with Anxiety if scoring > 62 based on linkage to the Generalized Anxiety Disorder-7 survey. Spearman correlations between the PROMIS scores were calculated. Bivariate statistics assessed differences in Anxiety and Depression scores between patients of different orthopedic services. Results: 20% of patients scored above the threshold to be considered affected by Anxiety. PROMIS Anxiety scores demonstrated a stronger correlation than Depression scores with Physical Function and Pain Interference scores. Patients with spine conditions reported the highest median Anxiety scores and were more likely to exceed the Anxiety threshold than patients presenting to sports or upper extremity surgeons. Conclusions: One in five new orthopedic patients reports Anxiety levels that may warrant intervention. This rate is heightened in patients needing spine care. Patient-reported Physical Function more strongly correlates with PROMIS Anxiety than Depression suggesting that the Anxiety CAT is a valuable addition to assess mental health among orthopedic patients. Level of Evidence: Diagnostic level III. © 2018 Springer International Publishing AG, part of Springer Nature

Author Keywords
Anxiety; Depression; Mental health; Orthopedic; Patient-reported

Document Type: Article in Press
Source: Scopus

"Prefrontal Recruitment Mitigates Risk-Taking Behavior in Human Immunodeficiency Virus-Infected Young Adults" (2018) Clinical Infectious Diseases

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

"Residual Symptoms after Treatment for Depression in Patients with Coronary Heart Disease" (2018) Psychosomatic Medicine

Residual Symptoms after Treatment for Depression in Patients with Coronary Heart Disease
(2018) Psychosomatic Medicine, 80 (4), pp. 385-392.

Carney, R.M., Freedland, K.E., Steinmeyer, B.C., Rubin, E.H., Rich, M.W.

Departments of Psychiatry Medicine, Washington University School of Medicine St, 4320 Forest Park Avenue, Suite 301, Saint Louis, MO, United States

Abstract
Objective Depression is associated with an increased risk of mortality in patients with coronary heart disease (CHD). The risk may be reduced in patients who remit with adequate treatment, but few patients achieve complete remission. The purpose of this study was to identify the symptoms that persist despite aggressive treatment for depression in patients with CHD. Methods One hundred twenty-five patients with stable CHD who met the DSM-IV criteria for a moderate-to-severe major depressive episode completed treatment with cognitive behavior therapy, either alone or combined with an antidepressant, for up to 16 weeks. Depression symptoms were assessed at baseline and after 16 weeks of treatment. Results The M (SD) Beck Depression Inventory scores were 30.0 (8.6) at baseline and 8.3 (7.5) at 16 weeks. Seventy seven (61%) of the participants who completed treatment met remission criteria (Hamilton Rating Scale for Depression ≤7) at 16 weeks. Loss of energy and fatigue were the most common posttreatment symptoms both in remitters (n = 44, 57%; n = 34, 44.2%) and nonremitters (n = 42, 87.5%; n = 35, 72.9%). These symptoms were not predicted by baseline depression severity, anxiety, demographic, or medical variables including inflammatory markers or cardiac functioning or by medical events during depression treatment. Conclusions Fatigue and loss of energy often persist in patients with CHD even after otherwise successful treatment for major depression. These residual symptoms may increase the risks of relapse and mortality. Development of effective interventions for these persistent symptoms is a priority for future research. © 2018 by the American Psychosomatic Society.

Author Keywords
Depressive disorder; residual symptoms.; treatment

Document Type: Article
Source: Scopus

"Adjusting after stroke: Changes in sense of purpose in life and the role of social support, relationship strain, and time" (2018) Journal of Health Psychology

Adjusting after stroke: Changes in sense of purpose in life and the role of social support, relationship strain, and time
(2018) Journal of Health Psychology, . Article in Press.

Lewis, N.A.^a ^b , Brazeau, H.^b , Hill, P.L.^c

^a University of Victoria, Canada
^b Carleton University, Canada
^c Washington University in St. Louis, USA

Abstract
It is unclear how the onset of a major health condition, such as a stroke, may impact sense of purpose long-term and whether social factors influence this change. We examined changes in purpose in 716 stroke patients (Mage = 72.09 years, 52.5% female) who participated in the Health and Retirement Study between 2006 and 2014. Multilevel growth modeling indicated that recent stroke patients’ sense of purpose declined over time relative to pre-stroke purpose, whereas those suffering stroke prior to baseline demonstrated relative stability. Furthermore, social support was associated with initial levels but not change in sense of purpose. © 2018, The Author(s) 2018.

Author Keywords
longitudinal; purpose in life; relationship strain; social support; stroke

Document Type: Article in Press
Source: Scopus

"Data-driven models of dominantly-inherited Alzheimer's disease progression" (2018) Brain

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

"Proximity to parental symptom onset and amyloid-β burden in sporadic Alzheimer disease" (2018) JAMA Neurology

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

"Preferential degradation of cognitive networks differentiates Alzheimer's disease from ageing" (2018) Brain

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

"Frontotemporal lobar degeneration (FTLD): Review and update for clinical neurologists" (2018) Current Alzheimer Research

Frontotemporal lobar degeneration (FTLD): Review and update for clinical neurologists
(2018) Current Alzheimer Research, 15 (6), pp. 511-530.

Hernández, I.^a , Fernández, M.-V.^b , Tàrraga, L.^a , Boada, M.^a , Ruiz, A.^a

^a Fundacio ACE, Memory Unit, Av Carlos III, 85 bis, Barcelona, Spain
^b Washington University, Saint Louis School of Medicine, Saint Louis, MO, United States

Abstract
Background: Frontotemporal Dementia (FTD) is a heterogeneous group of disorders and the second most frequent cause of early onset dementia making it the highest number of inherited cases. Review Summary: FTD is characterized by considerable variability in clinical, genetic and histopathologic features. Patients may present symptoms ranging from behavioural disturbances to different language disorders, with or without motor neuron disorders or associated parkinsonism. Atrophy in frontal and temporal lobes is the most relevant radiological finding. In the last 10 years, the knowledge of this clinical entity has undergone remarkable changes both genetically and histopathologically, which have served to establish more consistent clinical criteria. Until now, 10 genes causative of FTLD have been described and up to four different proteins causative of atrophy have been detected in aggregates. Conclusion: This review is mostly addressed to clinicians and aims to provide basic knowledge of these neurodegenerative disorders and clarify the complex FTD scenario. © 2018 Bentham Science Publishers.

Author Keywords
FTLD; Genotypes; Neurologist; Phenotypes; Proteotypes; Review

Document Type: Review
Source: Scopus

"Dual therapy for Aß amyloidosis in AD: A successful one-two combo" (2018) Journal of Experimental Medicine

Dual therapy for Aß amyloidosis in AD: A successful one-two combo
(2018) Journal of Experimental Medicine, 215 (5), pp. 1267-1268.

Patel, T.K., Holtzman, D.M.

Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University in St. Louis, St. Louis, MO, United States

Abstract
In this issue, Chiang et al. (https://doi.org/10.1084/jem.20171484) make a notable contribution to Alzheimer disease (AD) therapeutics in a thorough and rigorous study demonstrating superior efficacy of dual therapy against Aß in a mouse model of amyloid ß deposition. © 2018 Patel and Holtzman.

Document Type: Note
Source: Scopus

"White matter hyperintensities and the mediating role of cerebral amyloid angiopathy in dominantly-inherited Alzheimer’s disease" (2018) PLoS ONE

White matter hyperintensities and the mediating role of cerebral amyloid angiopathy in dominantly-inherited Alzheimer’s disease
(2018) PLoS ONE, 13 (5), art. no. e0195838, .

Lee, S.^a ^b , Zimmerman, M.E.^c ^d , Narkhede, A.^e , Nasrabady, S.E.^a ^e , Tosto, G.^e ^f , Meier, I.B.^e , Benzinger, T.L.S.^g , Marcus, D.S.^g , Fagan, A.M.^h , Fox, N.C.ⁱ , Cairns, N.J.^j , Holtzman, D.M.^h , Buckles, V.^h , Ghetti, B.^k , McDade, E.^h , Martins, R.N.^l , Saykin, A.J.^m , Masters, C.L.ⁿ , Ringman, J.M.^o , Fӧrster, S.^p , Schofield, P.R.^q , Sperling, R.A.^r , Johnson, K.A.^r , Chhatwal, J.P.^r , Salloway, S.^s , Correia, S.^t , Jack, C.R.^u , Weiner, M.^v , Bateman, R.J.^h , Morris, J.C.^h , Mayeux, R.^a ^e ^f ^w , Brickman, A.M.^e ^f ^w

^a Research Foundation for Mental Hygiene, Inc., New York, NY, United States
^b Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, United States
^c Psychology Department, Fordham University, Bronx, NY, United States
^d Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, United States
^e Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, United States
^f Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, United States
^g Department of Radiology, Washington University School of Medicine, Saint Louis, MO, United States
^h Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
ⁱ Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom
^j Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, United States
^k Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
^l Centre of Excellence of Alzheimer’s Disease Research and Care, School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Perth, Australia
^m Indiana Alzheimer Disease Center and Center for Neuroimaging, Department of Radiology and Imaging Science, Indiana University School of Medicine, Indianapolis, IN, United States
ⁿ Florey Institute, University of Melbourne, Parkville, Australia
^o Memory and Aging Center, Keck School of Medicine of University of Southern California, Los Angeles, CA, United States
^p German Center for Neurodegenerative Diseases (DZNE) München and Tübingen, Department of Nuclear Medicine, Technische Universität München (TUM), Munich, Germany
^q Neuroscience Research Australia and University of New South Wales, Sydney, Australia
^r Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^s Butler Hospital, Department of Neurology, Alpert Medical School, Brown University, Providence, RI, United States
^t Department of Psychiatry & Human Behavior, Alpert Medical School, Brown University, Providence, RI, United States
^u Department of Radiology, Mayo Clinic, Rochester, MN, United States
^v Department of Radiology and Biomedical Imaging, Center for Imaging of Neurodegenerative Diseases, San Francisco Veterans Affairs Medical Center, Departments of Psychiatry, Radiology, Medicine, and Neurology, University of California at San Francisco, San Francisco, CA, United States
^w Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, United States

Abstract
Introduction White matter hyperintensity (WMH) volume on MRI is increased among presymptomatic individuals with autosomal dominant mutations for Alzheimer’s disease (AD). One potential explanation is that WMH, conventionally considered a marker of cerebrovascular disease, are a reflection of cerebral amyloid angiopathy (CAA) and that increased WMH in this population is a manifestation of this vascular form of primary AD pathology. We examined whether the presence of cerebral microbleeds, a marker of CAA, mediates the relationship between WMH and estimated symptom onset in individuals with and without autosomal dominant mutations for AD. Participants and methods Participants (n = 175, mean age = 41.1 years) included 112 with an AD mutation and 63 first-degree non-carrier controls. We calculated the estimated years from expected symptom onset (EYO) and analyzed baseline MRI data for WMH volume and presence of cerebral microbleeds. Mixed effects regression and tests of mediation were used to examine microbleed and WMH differences between carriers and non-carriers and to test the whether the association between WMH and mutation status is dependent on the presence of microbleeds. Results Mutation carriers were more likely to have microbleeds than non-carriers (p<0.05) and individuals with microbleeds had higher WMH volume than those without (p<0.05). Total WMH volume was increased in mutation carriers compared with non-carriers, up to 20 years prior to EYO, after controlling for microbleed status, as we demonstrated previously. Formal testing of mediation demonstrated that 21% of the association between mutation status and WMH was mediated by presence of microbleeds (p = 0.03) but a significant direct effect of WMH remained (p = 0.02) after controlling for presence of microbleeds. Discussion Although there is some co-dependency between WMH and microbleeds, the observed increases in WMH among mutation carriers does not appear to be fully mediated by this marker of CAA. The findings highlight the possibility that WMH represent a core feature of AD independent of vascular forms of beta amyloid. © 2018 Lee 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

"Standard dose and dose-escalated radiation therapy are associated with favorable survival in select elderly patients with newly diagnosed glioblastoma" (2018) Journal of Neuro-Oncology

Standard dose and dose-escalated radiation therapy are associated with favorable survival in select elderly patients with newly diagnosed glioblastoma
(2018) Journal of Neuro-Oncology, 138 (1), pp. 155-162.

Jackson, W.C.^a , Tsien, C.I.^b , Junck, L.^c , Leung, D.^c , Hervey-Jumper, S.^d , Orringer, D.^d , Heth, J.^d , Wahl, D.R.^a , Spratt, D.E.^a , Cao, Y.^a , Lawrence, T.S.^a , Kim, M.M.^a

^a Department of Radiation Oncology, University of Michigan Medical Center, 1500 E. Medical Center Dr., Ann Arbor, MI, United States
^b Department of Radiation Oncology, School of Medicine Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Neuro-Oncology, University of Michigan, Ann Arbor, MI, United States
^d Department of Neurosurgery, University of Michigan, Ann Arbor, MI, United States

Abstract
We hypothesized elderly patients with good Karnofsky Performance Status (KPS) treated with standard dose or dose-escalated radiation therapy (SDRT/DERT) and concurrent temozolomide (TMZ) would have favorable overall survival (OS) compared to historical elderly patients treated with hypofractionated RT (HFRT). From 2004 to 2015, 66 patients age ≥ 60 with newly diagnosed, pathologically proven glioblastoma were treated with SDRT/DERT over 30 fractions with concurrent/adjuvant TMZ at a single institution. Kaplan–Meier methods and the log-rank test were used to assess OS and progression-free survival (PFS). Multivariate analysis (MVA) was performed using Cox Proportional-Hazards. Median follow-up was 12.6 months. Doses ranged from 60 to 81 Gy (median 66). Median KPS was 90 (range 60–100) and median age was 67 years (range 60–81), with 29 patients ≥ 70 years old. 32% underwent gross total resection (GTR). MGMT status was known in 28%, 42% of whom were methylated. Median PFS was 8.3 months (95% CI 6.9–11.0) and OS was 12.7 months (95% CI 9.7–14.1). Patients age ≥ 70 with KPS ≥ 90 had a median OS of 12.4 months. Median OS was 27.1 months for MGMT methylated patients. On MVA controlling for age, dose, KPS, MGMT, GTR, and adjuvant TMZ, younger age (HR 0.9, 95% CI 0.8–0.9, p < 0.01), MGMT methylation (HR:0.2, 95% CI 0.1–0.7, p = 0.01), and GTR (HR:0.5, 95% CI 0.3–0.9, p = 0.01) were associated with improved OS. Our findings do not support routine use of a standard 6-week course of radiation therapy in elderly patients with glioblastoma. However, a select group of elderly patients with excellent performance status and MGMT methylation or GTR may experience favorable survival with a standard 6-week course of treatment. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Dose and fractionation; Elderly; Glioblastoma; Outcomes; Radiation

Document Type: Article
Source: Scopus

"Shyness and Trajectories of Functional Network Connectivity Over Early Adolescence" (2018) Child Development

Shyness and Trajectories of Functional Network Connectivity Over Early Adolescence
(2018) Child Development, 89 (3), pp. 734-745. Cited 1 time.

Sylvester, C.M., Whalen, D.J., Belden, A.C., Sanchez, S.L., Luby, J.L., Barch, D.M.

Washington University School of Medicine, United States

Abstract
High shyness during early adolescence is associated with impaired peer relationships and risk for psychiatric disorders. Little is known, however, about the relation between shyness and trajectories of brain development over early adolescence. The current study longitudinally examined trajectories of resting-state functional connectivity (rs-fc) within four brain networks in 147 adolescents. Subjects underwent functional magnetic resonance imaging at three different time points, at average ages 10.5 (range = 7.8–13.0), 11.7 (range = 9.3–14.1), and 12.9 years (range = 10.1–15.2). Multilevel linear modeling indicated that high shyness was associated with a less steep negative slope of default mode network (DMN) rs-fc over early adolescence relative to low shyness. Less steep decreases in DMN rs-fc may relate to increased self-focus in adolescents with high shyness. © 2017 The Authors. Child Development © 2017 Society for Research in Child Development, Inc.

Document Type: Article
Source: Scopus

"Genome-wide association study identifies a novel locus for cannabis dependence" (2018) Molecular Psychiatry

Genome-wide association study identifies a novel locus for cannabis dependence
(2018) Molecular Psychiatry, 23 (5), pp. 1293-1302.

Agrawal, A.^a , Chou, Y.-L.^a , Carey, C.E.^b , Baranger, D.A.A.^b , Zhang, B.^c , Sherva, R.^d , Wetherill, L.^e , Kapoor, M.^f , Wang, J.-C.^f , Bertelsen, S.^f , Anokhin, A.P.^a , Hesselbrock, V.^g , Kramer, J.^h , Lynskey, M.T.ⁱ , Meyers, J.L.^j , Nurnberger, J.I.^e ^k ^l , Rice, J.P.^a , Tischfield, J.^m , Bierut, L.J.^a , Degenhardt, L.ⁿ , Farrer, L.A.^d , Gelernter, J.^o ^p , Hariri, A.R.^q , Heath, A.C.^a , Kranzler, H.R.^r , Madden, P.A.F.^a , Martin, N.G.^s , Montgomery, G.W.^t , Porjesz, B.^j , Wang, T.^u , Whitfield, J.B.^s , Edenberg, H.J.^e ^v , Foroud, T.^e , Goate, A.M.^f , Bogdan, R.^b , Nelson, E.C.^a

^a Department of Psychiatry, Washington University School of Medicine, 660 South Euclid, CB 8134, St Louis, MO, United States
^b Department of Psychological and Brain Sciences, Washington University in St. Louis, St Louis, MO, United States
^c Department of Developmental Biology, Washington University School of Medicine, St Louis, MO, United States
^d Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, United States
^e Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
^f Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^g Department of Psychiatry, University of Connecticut Health, Farmington, CT, United States
^h Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, United States
ⁱ King’s College London, Addictions Department, Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom
^j Downstate Medical Center, Department of Psychiatry, State University of New York, Brooklyn, NY, United States
^k Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, United States
^l Stark Neuroscience Center, Indiana University School of Medicine, Indianapolis, IN, United States
^m Rutgers, Department of Genetics, State University of New Jersey, New Brunswick, NJ, United States
ⁿ National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW, Australia
^o Yale University School of Medicine, Department of Psychiatry, New Haven, CT, United States
^p US Department of Veterans Affairs, West Haven, CT, United States
^q Department of Psychology and Neuroscience, Duke University, Durham, NC, United States
^r Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, VISN 4 MIRECC, Crescenz VAMC, Philadelphia, PA, United States
^s QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
^t Nstitute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
^u Department of Genetics, Washington University School of Medicine, St Louis, MO, United States
^v Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis, IN, United States

Abstract
Despite moderate heritability, only one study has identified genome-wide significant loci for cannabis-related phenotypes. We conducted meta-analyses of genome-wide association study data on 2080 cannabis-dependent cases and 6435 cannabis-exposed controls of European descent. A cluster of correlated single-nucleotide polymorphisms (SNPs) in a novel region on chromosome 10 was genome-wide significant (lowest P=1.3E-8). Among the SNPs, rs1409568 showed enrichment for H3K4me1 and H3K427ac marks, suggesting its role as an enhancer in addiction-relevant brain regions, such as the dorsolateral prefrontal cortex and the angular and cingulate gyri. This SNP is also predicted to modify binding scores for several transcription factors. We found modest evidence for replication for rs1409568 in an independent cohort of African American (896 cases and 1591 controls; P=0.03) but not European American (EA; 781 cases and 1905 controls) participants. The combined meta-analysis (3757 cases and 9931 controls) indicated trend-level significance for rs1409568 (P=2.85E-7). No genome-wide significant loci emerged for cannabis dependence criterion count (n=8050). There was also evidence that the minor allele of rs1409568 was associated with a 2.1% increase in right hippocampal volume in an independent sample of 430 EA college students (fwe-P=0.008). The identification and characterization of genome-wide significant loci for cannabis dependence is among the first steps toward understanding the biological contributions to the etiology of this psychiatric disorder, which appears to be rising in some developed nations. © The Author(s) 2018.

Document Type: Article
Source: Scopus

"Consumer sleep technology: An American academy of sleep medicine position statement" (2018) Journal of Clinical Sleep Medicine

Consumer sleep technology: An American academy of sleep medicine position statement
(2018) Journal of Clinical Sleep Medicine, 14 (5), pp. 877-880.

Khosla, S.^a , Deak, M.C.^b , Gault, D.^c , Goldstein, C.A.^d , Hwang, D.^e , Kwon, Y.^f , O’Hearn, D.^g , Schutte-Rodin, S.^h , Yurcheshen, M.ⁱ , Rosen, I.M.^h , Kirsch, D.B.^j , Chervin, R.D.^d , Carden, K.A.^k , Ramar, K.^l , Nisha Aurora, R.^m , Kristo, D.A.ⁿ , Malhotra, R.K.^o , Martin, J.L.^p ^q , Olson, E.J.^l , Rosen, C.L.^r , Rowley, J.A.^s

^a North Dakota Center for Sleep, Fargo, ND, United States
^b EviCore Healthcare, Bluffton, SC, United States
^c Greenville Health System, University of South Carolina, Greenville, SC, United States
^d University of Michigan Sleep Disorders Center, Ann Arbor, MI, United States
^e Southern California Permanente Medical Group, Kaiser Permanente Fontana Sleep Disorders Center, Fontana, CA, United States
^f Cardiovascular Division, Department of Medicine, University of Virginia, Charlottesville, VA, United States
^g Department of Medicine, University of Washington, Seattle, WA, United States
^h Division of Sleep Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
ⁱ UR Medicine Sleep Center, Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY, United States
^j Carolinas Healthcare Medical Group Sleep Services, Charlotte, NC, United States
^k Saint Thomas Medical Partners-Sleep Specialists, Nashville, TN, United States
^l Division of Pulmonary and Critical Care Medicine, Center for Sleep Medicine, Mayo Clinic, Rochester, MN, United States
^m Johns Hopkins University, School of Medicine, Baltimore, MD, United States
ⁿ University of Pittsburgh, Pittsburgh, PA, United States
^o Washington University Sleep Center, Washington University, St. Louis, MO, United States
^p Veteran Affairs Greater Los Angeles Health System, North Hills, CA, United States
^q David Geffen School of Medicine, UCLA, Los Angeles, CA, United States
^r Department of Pediatrics, Case Western Reserve University, University Hospitals-Cleveland Medical Center, Cleveland, OH, United States
^s Wayne State University, Detroit, MI, United States

Abstract
Consumer sleep technologies (CSTs) are widespread applications and devices that purport to measure and even improve sleep. Sleep clinicians may frequently encounter CST in practice and, despite lack of validation against gold standard polysomnography, familiarity with these devices has become a patient expectation. This American Academy of Sleep Medicine position statement details the disadvantages and potential benefts of CSTs and provides guidance when approaching patient-generated health data from CSTs in a clinical setting. Given the lack of validation and United States Food and Drug Administration (FDA) clearance, CSTs cannot be utilized for the diagnosis and/or treatment of sleep disorders at this time. However, CSTs may be utilized to enhance the patient-clinician interaction when presented in the context of an appropriate clinical evaluation. The ubiquitous nature of CSTs may further sleep research and practice. However, future validation, access to raw data and algorithms, and FDA oversight are needed. © 2018 American Academy of Sleep Medicine. All Rights Reserved.

Author Keywords
Consumer sleep technology; Patient-generated health data (PGHD); Polysomnography

Document Type: Article
Source: Scopus

"Tau positron emission tomography in autosomal dominant Alzheimer disease small windows, big picture" (2018) JAMA Neurology

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

"Physical therapy and deep brain stimulation in Parkinson's Disease: Protocol for a pilot randomized controlled trial" (2018) Pilot and Feasibility Studies

Physical therapy and deep brain stimulation in Parkinson’s Disease: Protocol for a pilot randomized controlled trial
(2018) Pilot and Feasibility Studies, 4 (1), art. no. 54, .

Duncan, R.P.^a ^b , Van Dillen, L.R.^a ^c , Garbutt, J.M.^d ^e , Earhart, G.M.^a ^b ^f , Perlmutter, J.S.^a ^b ^f ^g ^h

^a Washington University School of Medicine in Saint Louis, Program in Physical Therapy, Campus Box 8502, 4444 Forest Park Blvd, St. Louis, MO, United States
^b Washington University School of Medicine in Saint Louis, Department of Neurology, St. Louis, MO, United States
^c Washington University School of Medicine in Saint Louis, Department of Orthopaedic Surgery, St. Louis, MO, United States
^d Washington University School of Medicine in Saint Louis, Department of Medicine, St. Louis, MO, United States
^e Washington University School of Medicine in Saint Louis, Department of Pediatrics, St. Louis, MO, United States
^f Washington University School of Medicine in Saint Louis, Department of Neuroscience, St. Louis, MO, United States
^g Washington University School of Medicine in Saint Louis, Department of Radiology, St. Louis, MO, United States
^h Washington University School of Medicine in Saint Louis, Program in Occupational Therapy, St. Louis, MO, United States

Abstract
Background: Subthalamic nucleus deep brain stimulation (STN-DBS) reduces tremor, muscle stiffness, and bradykinesia in people with Parkinson’s Disease (PD). Walking speed, known to be reduced in PD, typically improves after surgery; however, other important aspects of gait may not improve. Furthermore, balance may worsen and falls may increase after STN-DBS. Thus, interventions to improve balance and gait could reduce morbidity and improve quality of life following STN-DBS. Physical therapy (PT) effectively improves balance and gait in people with PD, but studies on the effects of PT have not been extended to those treated with STN-DBS. As such, the efficacy, safety, and feasibility of PT in this population remain to be determined. The purpose of this pilot study is to address these unmet needs. We hypothesize that PT designed to target balance and gait impairment will be effective, safe, and feasible in this population. Methods/design: Participants with PD treated with STN-DBS will be randomly assigned to either a PT or control group. Participants assigned to PT will complete an 8-week, twice-weekly PT program consisting of exercises designed to improve balance and gait. Control group participants will receive the current standard of care following STN-DBS, which does not include prescription of PT. The primary aim is to assess preliminary efficacy of PT on balance (Balance Evaluation Systems Test). A secondary aim is to assess efficacy of PT on gait (GAITRite instrumented walkway). Participants will be assessed OFF medication/OFF stimulation and ON medication/ON stimulation at baseline and at 8 and 12 weeks after baseline. Adverse events will be measured over the duration of the study, and adherence to PT will be measured to determine feasibility. Discussion: To our knowledge, this will be the first study to explore the preliminary efficacy, safety, and feasibility of PT for individuals with PD with STN-DBS. If the study suggests potential efficacy, then this would justify larger trials to test effectiveness and safety of PT for those with PD with STN-DBS. © 2018 The Author(s).

Author Keywords
Balance; Deep brain stimulation; Gait; Parkinson’s disease; Physical therapy

Document Type: Article
Source: Scopus

"Red blood cell antibody-induced anemia causes differential degrees of tissue hypoxia in kidney and brain" (2018) American Journal of Physiology – Regulatory Integrative and Comparative Physiology

Red blood cell antibody-induced anemia causes differential degrees of tissue hypoxia in kidney and brain
(2018) American Journal of Physiology – Regulatory Integrative and Comparative Physiology, 314 (4), pp. R611-R622. Cited 1 time.

Mistry, N.^a ^b , Mazer, C.D.^a ^b ^c , Sled, J.G.^d ^e , Lazarus, A.H.^c ^f , Cahill, L.S.^d , Solish, M.^c , Zhou, Y.-Q.^d , Romanova, N.^g , Hare, A.G.M.^c , Doctor, A.^h , Fisher, J.A.^b ⁱ , Brunt, K.R.^j , Simpson, J.A.^g , Hare, G.M.T.^a ^b ^c ^k

^a Department of Anesthesia, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada
^b Department of Physiology, University of Toronto, Toronto, ON, Canada
^c Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, ON, Canada
^d Mouse Imaging Centre, The Hospital for Sick Children, Toronto, ON, Canada
^e Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
^f Canadian Blood Services Centre for Innovation, Ottawa, ON, Canada
^g Department of Human Health and Nutritional Sciences and Cardiovascular Research Group, University of Guelph, Guelph, ON, Canada
^h Department of Pediatrics, Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis, St. Louis, MO, United States
ⁱ Department of Anesthesia, Toronto General Hospital, University of Toronto, Toronto, ON, Canada
^j Department of Pharmacology, Dalhousie University, Saint John, NB, Canada
^k St. Michael’s Hospital Center of Excellence in Patient Blood Management, University of Toronto, Toronto, ON, Canada

Abstract
Moderate anemia is associated with increased mortality and morbidity, including acute kidney injury (AKI), in surgical patients. A red blood cell (RBC)-specific antibody model was utilized to determine whether moderate subacute anemia could result in tissue hypoxia as a potential mechanism of injury. Cardiovascular and hypoxic cellular responses were measured in transgenic mice capable of expressing hypoxia-inducible factor-1β (HIF-1β)/luciferase activity in vivo. Antibody-mediated anemia was associated with mild intravascular hemolysis (6 h) and splenic RBC sequestration (day 4), resulting in a nadir hemoglobin concentration of 89 ± 13 g/l on day 4. At this time point, renal tissue oxygen tension (PtO2) was decreased in anemic mice relative to controls (13.1 ± 4.3 vs. 20.8 ± 3.7 mmHg, P < 0.001). Renal tissue hypoxia was associated with an increase in HIF/luciferase expression in vivo (P = 0.04) and a 20-fold relative increase in renal erythropoietin mRNA transcription (P < 0.001) but no increase in renal blood flow (P = 0.67). By contrast, brain PtO2was maintained in anemic mice relative to controls (22.7 ± 5.2 vs. 23.4 ± 9.8 mmHg, P = 0.59) in part because of an increase in internal carotid artery blood flow (80%, P < 0.001) and preserved cerebrovascular reactivity. Despite these adaptive changes, an increase in brain HIF-dependent mRNA levels was observed (erythropoietin: P < 0.001; heme oxygenase-1: P = 0.01), providing evidence for subtle cerebral tissue hypoxia in anemic mice. These data demonstrate that moderate subacute anemia causes significant renal tissue hypoxia, whereas adaptive cerebrovascular responses limit the degree of cerebral tissue hypoxia. Further studies are required to assess whether hypoxia is a mechanism for acute kidney injury associated with anemia. © 2018 American Physiological Society. All rights reserved.

Author Keywords
Acute kidney injury; Anemia-induced tissue hypoxia; Subacute anemia

Document Type: Article
Source: Scopus

"Reinfection after treatment of first cerebrospinal fluid shunt infection: A prospective observational cohort study" (2018) Journal of Neurosurgery: Pediatrics

Reinfection after treatment of first cerebrospinal fluid shunt infection: A prospective observational cohort study
(2018) Journal of Neurosurgery: Pediatrics, 21 (4), pp. 346-358.

Simon, T.D.^a ^c , Kronman, M.P.^a ^c , Whitlock, K.B.^c , Gove, N.E.^c , Mayer-Hamblett, N.^a ^c , Browd, S.R.^b , Cochrane, D.D.^d , Holubkov, R.^e , Kulkarni, A.V.^d , Langley, M.^f , Limbrick, D.D.^g , Luerssen, T.G.^h , Oakes, W.J.ⁱ , Riva-Cambrin, J.^j , Rozzelle, C.ⁱ , Shannon, C.^k , Tamber, M.^l , Wellons, J.C.^k , Whitehead, W.E.^h , Kestle, J.R.W.^f

^a Department of Pediatrics, University of Washington, Seattle Children’s Hospital, Seattle, WA, United States
^b Department of Neurosurgery, University of Washington, Seattle Children’s Hospital, Seattle, WA, United States
^c Seattle Children’s Research Institute, Seattle, WA, United States
^d Division of Neurosurgery, Hospital for Sick Children, University of Toronto, Ontario, Canada
^e Department of Pediatrics, University of Utah, Salt Lake City, UT, United States
^f Division of Pediatric Neurosurgery, Primary Children’s Hospital, Department of Neurosurgery, University of Utah, Salt Lake City, UT, United States
^g Department of Neurosurgery, St. Louis Children’s Hospital, Washington University, St. Louis, MO, United States
^h Division of Pediatric Neurosurgery, Texas Children’s Hospital, Department of Neurosurgery, Baylor College of Medicine, Houston, TX, United States
ⁱ Section of Pediatric Neurosurgery, Children’s of Alabama, Division of Neurosurgery, University of Alabama, Birmingham, AL, United States
^j Department of Clinical Neurosciences, University of Calgary, Alberta, Canada
^k Department of Neurosurgery, Vanderbilt University, Nashville, TN, United States
^l Division of Neurosurgery, Children’s Hospital of PittsburghPA, United States

Abstract
OBJECTIVE CSF shunt infection requires both surgical and antibiotic treatment. Surgical treatment includes either total shunt removal with external ventricular drain (EVD) placement followed by new shunt insertion, or distal shunt externalization followed by new shunt insertion once the CSF is sterile. Antibiotic treatment includes the administration of intravenous antibiotics. The Hydrocephalus Clinical Research Network (HCRN) registry provides a unique opportunity to understand reinfection following treatment for CSF shunt infection. This study examines the association of surgical and antibiotic decisions in the treatment of first CSF shunt infection with reinfection. METHODS A prospective cohort study of children undergoing treatment for first CSF infection at 7 HCRN hospitals from April 2008 to December 2012 was performed. The HCRN consensus definition was used to define CSF shunt infection and reinfection. The key surgical predictor variable was surgical approach to treatment for CSF shunt infection, and the key antibiotic treatment predictor variable was intravenous antibiotic selection and duration. Cox proportional hazards models were constructed to address the time-varying nature of the characteristics associated with shunt surgeries. RESULTS Of 233 children in the HCRN registry with an initial CSF shunt infection during the study period, 38 patients (16%) developed reinfection over a median time of 44 days (interquartile range [IQR] 19–437). The majority of initial CSF shunt infections were treated with total shunt removal and EVD placement (175 patients; 75%). The median time between infection surgeries was 15 days (IQR 10–22). For the subset of 172 infections diagnosed by CSF culture, the mean ± SD duration of antibiotic treatment was 18.7 ± 12.8 days. In all Cox proportional hazards models, neither surgical approach to infection treatment nor overall intravenous antibiotic duration was independently associated with reinfection. The only treatment decision independently associated with decreased infection risk was the use of rifampin. While this finding did not achieve statistical significance, in all 5 Cox proportional hazards models both surgical approach (other than total shunt removal at initial CSF shunt infection) and nonventriculoperitoneal shunt location were consistently associated with a higher hazard of reinfection, while the use of ultrasound was consistently associated with a lower hazard of reinfection. CONCLUSIONS Neither surgical approach to treatment nor antibiotic duration was associated with reinfection risk. While these findings did not achieve statistical significance, surgical approach other than total removal at initial CSF shunt infection was consistently associated with a higher hazard of reinfection in this study and suggests the feasibility of controlling and standardizing the surgical approach (shunt removal with EVD placement). Considerably more variation and equipoise exists in the duration and selection of intravenous antibiotic treatment. Further consideration should be given to the use of rifampin in the treatment of CSF shunt infection. High-quality studies of the optimal duration of antibiotic treatment are critical to the creation of evidence-based guidelines for CSF shunt infection treatment. © AANS 2018.

Author Keywords
Antibiotic; Cerebrospinal; Hydrocephalus; Infection; Reinfection; Shunt; Treatment

Document Type: Article
Source: Scopus

"Differential solvation of intrinsically disordered linkers drives the formation of spatially organized droplets in ternary systems of linear multivalent proteins" (2018) New Journal of Physics

Differential solvation of intrinsically disordered linkers drives the formation of spatially organized droplets in ternary systems of linear multivalent proteins
(2018) New Journal of Physics, 20 (4), art. no. 045002, .

Harmon, T.S.^a ^b , Holehouse, A.S.^b , Pappu, R.V.^b

^a Max-Planck-Institute for the Physics of Complex Systems, Dresden, Germany
^b Department of Biomedical Engineering and Center for Biological Systems Engineering, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Intracellular biomolecular condensates are membraneless organelles that encompass large numbers of multivalent protein and nucleic acid molecules. The bodies assemble via a combination of liquid-liquid phase separation and gelation. A majority of condensates included multiple components and show multilayered organization as opposed to being well-mixed unitary liquids. Here, we put forward a simple thermodynamic framework to describe the emergence of spatially organized droplets in multicomponent systems comprising of linear multivalent polymers also known as associative polymers. These polymers, which mimic proteins and/or RNA have the architecture of domains or motifs known as stickers that are interspersed by flexible spacers known as linkers. Using a minimalist numerical model for a four-component system, we have identified features of linear multivalent molecules that are necessary and sufficient for generating spatially organized droplets. We show that differences in sequence-specific effective solvation volumes of disordered linkers between interaction domains enable the formation of spatially organized droplets. Molecules with linkers that are preferentially solvated are driven to the interface with the bulk solvent, whereas molecules that have linkers with negligible effective solvation volumes form cores in the core-shell architectures that emerge in the minimalist four-component systems. Our modeling has relevance for understanding the physical determinants of spatially organized membraneless organelles. © 2018 The Author(s). Published by IOP Publishing Ltd on behalf of Deutsche Physikalische Gesellschaft.

Author Keywords
Biomolecular condensates; Intrinsically disordered linkers; Lattice model; Multiphase equilibria; Spatially organized dropelts

Document Type: Article
Source: Scopus

"Effects of exercise on gait and motor imagery in people with Parkinson disease and freezing of gait" (2018) Parkinsonism and Related Disorders

Effects of exercise on gait and motor imagery in people with Parkinson disease and freezing of gait
(2018) Parkinsonism and Related Disorders, . Article in Press.

Myers, P.S.^a , McNeely, M.E.^a ^b , Pickett, K.A.^d , Duncan, R.P.^a ^b , Earhart, G.M.^a ^b ^c

^a Program in Physical Therapy, Washington University in St. Louis School of Medicine, Campus Box 8502, 4444 Forest Park Blvd, Suite 11101, St. Louis, MO, United States
^b Department of Neurology, Washington University in St. Louis School of Medicine, Campus Box 8111, 660 S. Euclid, St. Louis, MO, United States
^c Department of Neuroscience, Washington University in St. Louis School of Medicine, Campus Box 8108, 660 S. Euclid, St. Louis, MO, United States
^d Occupational Therapy Program, Department of Kinesiology, University of Wisconsin- Madison School of Education, Unit II Gym, 2000 Observatory Drive, Madison, WI, United States

Abstract
Introduction: Exercise improves gait in Parkinson disease (PD), but whether exercise differentially affects people with PD with (freezers) and without freezing of gait (non-freezers) remains unclear. This study examines exercise’s effects on gait performance, neural correlates related to these effects, and potential neural activation differences between freezers and non-freezers during motor imagery (MI) of gait. Methods: Thirty-seven participants from a larger exercise intervention completed behavioral assessments and functional magnetic resonance imaging (fMRI) scans before and after a 12-week exercise intervention. Gait performance was characterized using gait velocity and stride length, and a region of interest (ROI) fMRI analysis examined task-based blood oxygen-level dependent (BOLD) signal changes of the somatomotor network (SMN) during MI of forward (IMG-FWD) and backward (IMG-BWD) gait. Results: Velocity (F(1,34) = 55.04, p < 0.001) and stride length (F(1,34) = 77.58, p < 0.001) were significantly lower for backward versus forward walking in all participants. The ROI analysis showed freezers had lower BOLD signal compared to non-freezers in the cerebellum (F(1,32) = 7.01, p = 0.01), primary motor (left: F(1,32) = 7.09, p = 0.01; right: F(1,32) = 7.45, p = 0.01), and primary sensory (left: F(1,32) = 9.59, p = 0.004; right: F(1,32) = 8.18, p = 0.007) cortices during IMG-BWD only. The evidence suggests the exercise intervention did not affect gait or BOLD signal during MI. Conclusion: While all participants had significantly slower and shorter backward velocity and stride length, respectively, the exercise intervention had no effect. Similarly, BOLD signal during MI did not change with exercise; however, freezers had significantly lower BOLD signal during IMG-BWD compared to non-freezers. This suggests potential decreased recruitment of the SMN during MI of gait in freezers. © 2018 Elsevier Ltd

Author Keywords
Cerebellum; Freezing of gait; Neuroimaging; Parkinson disease

Document Type: Article in Press
Source: Scopus

"MicroRNA signature of central nervous system-infiltrating dendritic cells in an animal model of multiple sclerosis" (2018) Immunology

MicroRNA signature of central nervous system-infiltrating dendritic cells in an animal model of multiple sclerosis
(2018) Immunology, . Article in Press.

Hoye, M.L.^a , Archambault, A.S.^a , Gordon, T.M.^a , Oetjen, L.K.^b , Cain, M.D.^b , Klein, R.S.^b ^c , Crosby, S.D.^d , Kim, B.S.^b ^e ^f , Miller, T.M.^a ^c , Wu, G.F.^a ^c ^e

^a Department of Neurology Washington University School of Medicine St Louis, MOUSA
^b Department of Medicine Washington University School of Medicine St Louis, MOUSA
^c The Hope Center for Neurological Disorders Washington University School of Medicine St Louis, MOUSA
^d Genome Technology Access Center Washington University School of Medicine St Louis, MOUSA
^e Department of Immunology and Pathology Washington University School of Medicine St Louis, MOUSA
^f Center for the Study of Itch Washington University School of Medicine St Louis, MO USA

Abstract
Innate immune cells are integral to the pathogenesis of several diseases of the central nervous system (CNS), including multiple sclerosis (MS). Dendritic cells (DCs) are potent CD11c+ antigen-presenting cells that are critical regulators of adaptive immune responses, particularly in autoimmune diseases such as MS. The regulation of DC function in both the periphery and CNS compartment has not been fully elucidated. One limitation to studying the role of CD11c+ DCs in the CNS is that microglia can upregulate CD11c during inflammation, making it challenging to distinguish bone marrow-derived DCs (BMDCs) from microglia. Selective expression of microRNAs (miRNAs) has been shown to distinguish populations of innate cells and regulate their function within the CNS during neuro-inflammation. Using the experimental autoimmune encephalomyelitis (EAE) murine model of MS, we characterized the expression of miRNAs in CD11c+ cells using a non-biased murine array. Several miRNAs, including miR-31, were enriched in CD11c+ cells within the CNS during EAE, but not LysM+ microglia. Moreover, to distinguish CD11c+ DCs from microglia that upregulate CD11c, we generated bone marrow chimeras and found that miR-31 expression was specific to BMDCs. Interestingly, miR-31-binding sites were enriched in mRNAs downregulated in BMDCs that migrated into the CNS, and a subset was confirmed to be regulated by miR-31. Finally, miR-31 was elevated in DCs migrating through an in vitro blood-brain barrier. Our findings suggest miRNAs, including miR-31, may regulate entry of DCs into the CNS during EAE, and could potentially represent therapeutic targets for CNS autoimmune diseases such as MS. © 2018 John Wiley & Sons Ltd.

Author Keywords
Dendritic cells; MicroRNAs; Multiple sclerosis; Neuroinflammation

Document Type: Article in Press
Source: Scopus

"The Microglial Response to Neurodegenerative Disease" (2018) Advances in Immunology

The Microglial Response to Neurodegenerative Disease
(2018) Advances in Immunology, . Article in Press.

Song, W.M., Colonna, M.

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

Abstract
Microglia are a subset of tissue macrophages that constitute the major immune cell type of the central nervous system. These cells have long been known to change their morphology and functions in response to various neurological insults. Recently, a plethora of unbiased transcriptomics studies have revealed that across a broad spectrum of neurodegeneration-like disease models, microglia adopt a similar activation signature and perform similar functions. Despite these commonalities in response, the role of microglia has been described as both positive and negative in different murine disease models. In humans, genetic association studies have revealed strong connections between microglia genes and various neurodegenerative diseases, and mechanistic investigations of these mutations have added another layer of complexity. Here, we provide an overview of studies that have built a case for a common microglial response to neurodegeneration and discuss pathways that may be important to initiate and sustain this response; delineate the multifaceted functions of activated microglia spanning different diseases; and discuss insights from studying genes associated with disease in humans. We argue that strong evidence causally links activated microglia function to neurodegeneration and discuss what seems to be a conflict between mouse models and human genetics. © 2018 Elsevier Inc.

Author Keywords
Alzheimer’s disease; DAM; Microglia; Neurodegeneration; Neuroimmunology; Neuroinflammation

Document Type: Article in Press
Source: Scopus

"Improving mental health among ultra-poor children: Two-year outcomes of a cluster-randomized trial in Burkina Faso" (2018) Social Science and Medicine

Improving mental health among ultra-poor children: Two-year outcomes of a cluster-randomized trial in Burkina Faso
(2018) Social Science and Medicine, . Article in Press.

Ismayilova, L.^a , Karimli, L.^b , Sanson, J.^c , Gaveras, E.^d , Nanema, R.^e , Tô-Camier, A.^e , Chaffin, J.^f

^a The University of Chicago, Chicago, United States
^b The University of California, Los Angeles, Los Angeles, United States
^c Trickle Up, New York, United States
^d Washington University in St. Louis, St. Louis, United States
^e Trickle Up, Ouagadougou, Burkina Faso
^f Women’s Refugee Committee, New York, United States

Abstract
Rationale: There is limited evidence about interventions improving child mental health in francophone West Africa. Behavioral mental health interventions alone may have limited effects on children’s emotional well-being in families living in abject poverty, especially in low-income countries. Objective: This study tests the effects of economic intervention, alone and in combination with a family-focused component, on the mental health of children from ultra-poor households in rural Burkina Faso. Methods: The three-arm cluster randomized trial included children in the age range of 10–15 years old (N = 360), from twelve villages in Nord region of Burkina Faso (ClinicalTrial.gov ID: NCT02415933). Villages were randomized (4 villages/120 households per arm) to the waitlist arm, the economic intervention utilizing the Graduation approach (Trickle Up/TU arm), or to the economic strengthening plus family coaching component (TU + arm). Intervention effects were tested using repeated-measures mixed-effects regressions that account for the clustered nature of the data. Results: Children from the TU + arm showed a reduction in depressive symptoms at 12 months (medium effect size Cohen’s d = −0.41, p =.001) and 24 months (d = −0.39, p =.025), compared to the control condition and the economic intervention alone (at 12 months d = −0.22, p =.020). Small effect size improvements in self-esteem were detected in the TU + group, compared to the control arm at 12 months (d = 0.21) and to the TU arm at 24 months (d = 0.21). Trauma symptoms significantly reduced in the TU + group at 12 months (Incidence Risk Ratio/IRR = 0.62, 95% CI = 0.41, 0.92, p =.042), compared to the control group. Conclusion: Integrating psychosocial intervention involving all family members with economic empowerment strategies may be an innovative approach for improving emotional well-being among children living in extreme poverty. © 2018 Elsevier Ltd

Author Keywords
Child; Depression; Graduation approach; Low-income population; Prevention; Trauma

Document Type: Article in Press
Source: Scopus

"Utilizing the Centiloid scale in cross-sectional and longitudinal PiB PET studies" (2018) NeuroImage: Clinical

Utilizing the Centiloid scale in cross-sectional and longitudinal PiB PET studies
(2018) NeuroImage: Clinical, 19, pp. 406-416.

Su, Y.^a ^c , Flores, S.^a , Hornbeck, R.C.^a , Speidel, B.^e , Vlassenko, A.G.^a ^c , Gordon, B.A.^a ^c , Koeppe, R.A.^f , Klunk, W.E.^g , Xiong, C.^c ^d , Morris, J.C.^b ^c , Benzinger, T.L.S.^a ^c

^a Department of Radiology, Washington University School of Medicine, Saint Louis, MO, United States
^b Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
^c Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, United States
^d Division of Biostatistics, Washington University School of Medicine, Saint Louis, MO, United States
^e Department of Radiology & Biomedical Imaging, University of California, San Francisco, CA, United States
^f Department of Radiology, University of Michigan, Ann Arbor, MI, United States
^g Department of Neurology, University of Pittsburgh, Pittsburgh, PA, United States

Abstract
Amyloid imaging is a valuable tool for research and diagnosis in dementing disorders. Successful use of this tool is limited by the lack of a common standard in the quantification of amyloid imaging data. The Centiloid approach was recently proposed to address this problem and in this work, we report our implementation of this approach and evaluate the impact of differences in underlying image analysis methodologies using both cross-sectional and longitudinal datasets. The Centiloid approach successfully converts quantitative amyloid burden measurements into a common Centiloid scale (CL) and comparable dynamic range. As expected, the Centiloid values derived from different analytical approaches inherit some of the inherent benefits and drawbacks of the underlying approaches, and these differences result in statistically significant (p < 0.05) differences in the variability and group mean values. Because of these differences, even after expression in CL, the 95% specificity amyloid positivity thresholds derived from different analytic approaches varied from 5.7 CL to 11.9 CL, and the reliable worsening threshold varied from −2.0 CL to 11.0 CL. Although this difference is in part due to the dependency of the threshold determination methodology on the statistical characteristics of the measurements. When amyloid measurements obtained from different centers are combined for analysis, one should not expect Centiloid conversion to eliminate all the differences in amyloid burden measurements due to variabilities in underlying acquisition protocols and analysis techniques. © 2018 The Authors

Author Keywords
Amyloid imaging; Centiloid; PET; PiB

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

"Role of sirtuins in retinal function under basal conditions" (2018) Advances in Experimental Medicine and Biology

Role of sirtuins in retinal function under basal conditions
(2018) Advances in Experimental Medicine and Biology, 1074, pp. 561-567.

Lin, J.B.^a ^b , Kubota, S.^a , Mostoslavsky, R.^c , Apte, R.S.^a ^d ^e

^a Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
^b Neuroscience Graduate Program, Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, United States
^c Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, United States
^d Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Sirtuins are NAD+-dependent enzymes that govern cellular homeostasis by regulating the acylation status of their diverse target proteins. We recently demonstrated that both rod and cone photoreceptors rely on NAMPT-mediated NAD+ biosynthesis to meet their energetic requirements. Moreover, we found that this NAD+-dependent retinal homeostasis relies, in part, on maintenance of optimal activity of the mitochondrial sirtuins and of SIRT3 in particular. Nonetheless, it is unknown whether other sirtuin family members also play important roles in retinal homeostasis. Our results suggest that SIRT1, SIRT2, SIRT4, and SIRT6 are dispensable for retinal survival at baseline, as individual deletion of each of these sirtuins does not cause retinal degeneration by fundus biomicroscopy or retinal dysfunction by ERG. These findings have significant implications and inform future studies investigating the mechanisms underlying the central role of NAD+ biosynthesis in retinal survival and function. © 2018, Springer International Publishing AG, part of Springer Nature.

Author Keywords
NAD+; Neurodegeneration; Photoreceptors; Retina; Retinal degeneration; Sirtuins

Document Type: Book Chapter
Source: Scopus

"Childhood trauma is associated with poorer cognitive performance in older adults" (2018) Journal of Clinical Psychiatry

Childhood trauma is associated with poorer cognitive performance in older adults
(2018) Journal of Clinical Psychiatry, 79 (1), art. no. 16m11021, .

Petkus, A.J.^a , Lenze, E.J.^b , Butters, M.A.^c , Twamley, E.W.^d ^e , Wetherell, J.L.^e ^f

^a Department of Neurology, University of Southern California, 1520 San Pablo St, Ste 3000, Los Angeles, CA, United States
^b Healthy Mind Laboratory, Department of Psychiatry, Washington University, St Louis, MO, United States
^c Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
^d Center of Excellence for Stress and Mental Health, VA San Diego Healthcare System, San Diego, CA, United States
^e Department of Psychiatry, University of California, San Diego, CA, United States
^f VA San Diego Healthcare System, San Diego, CA, United States

Abstract
Objective: Childhood trauma is common and associated with both worse cognitive performance and disruption to the hypothalamic-pituitary-adrenal axis in younger adults. The extent to which these associations persist into older adulthood remains unknown. The aim of this study was to investigate self-reported childhood trauma in relation to cognitive performance, and the extent to which cortisol explained this association, in 2 independent samples of older adults. Methods: In this cross-sectional study, participants in the discovery sample (N = 76) consisted of older adults with a DSM-IV diagnosis of generalized anxiety disorder (N = 57) and age-equated psychiatrically healthy comparison subjects (N = 19) who were referred largely through primary care clinics between 2004-2006. The replication sample (N = 48) consisted of older adults with DSM-IV anxiety or depressive disorders recruited between 2012-2013. Participants were administered the Early Trauma Inventory Self-Report-Short Form and a neuropsychological assessment (primary outcome). Results: Across both samples, childhood trauma was significantly associated with worse performance on measures of processing speed, attention, and executive functioning. The effect of trauma exposure was stronger when general, physical, and sexual traumatic events were examined specifically (all P < .05). Childhood trauma was not associated with cortisol levels, and cortisol did not explain the association between trauma and cognitive functioning. Conclusions: Self-reported traumatic events experienced in childhood are associated with poorer cognitive performance in anxious and depressed older adults. Findings demonstrate a deleterious impact of childhood trauma on brain health in old age. © Copyright 2017 Physicians Postgraduate Press, Inc.

Document Type: Article
Source: Scopus

"Enhanced recovery after surgery in children: Promising, evidence-based multidisciplinary care" (2018) Paediatric Anaesthesia

Enhanced recovery after surgery in children: Promising, evidence-based multidisciplinary care
(2018) Paediatric Anaesthesia, . Article in Press.

Rove, K.O.^a , Edney, J.C.^b , Brockel, M.A.^c

^a Division of Pediatric Urology St. Louis Children’s Hospital Washington University School of Medicine St. Louis, MO USA
^b Department of Anesthesiology Children’s Healthcare of Atlanta Emory University School of Medicine Atlanta, GA USA
^c Department of Anesthesiology Children’s Hospital Colorado University of Colorado School of Medicine Aurora, CO USA

Abstract
Enhanced recovery after surgery (ERAS) is a multimodal approach to the care of the surgical patient focused on reducing the stress response and associated physiologic changes that accompany surgery. Over the past 20 years, ERAS programs have been found to result in reduced LOS and complications in adult patients. Despite abundant adult literature describing implementation and outcomes of enhanced recovery programs, pediatric data in this area is sparse. This educational review describes the history and elements of ERAS protocols, reviews the available evidence in adult and pediatric populations, compares and contrasts ERAS with the PSH, and offers strategies for implementation and ideas for future directions of ERAS in children. © 2018 John Wiley & Sons Ltd.

Author Keywords
Bowel preparation solutions; Fluid therapy; Nonsteroidal anti-inflammatory drugs (NSAIDS); Opioids; Perioperative care; Surgical stress

Document Type: Article in Press
Source: Scopus

"Effective connectivity measured using optogenetically evoked hemodynamic signals exhibits topography distinct from resting state functional connectivity in the mouse" (2018) Cerebral Cortex

Effective connectivity measured using optogenetically evoked hemodynamic signals exhibits topography distinct from resting state functional connectivity in the mouse
(2018) Cerebral Cortex, 28 (1), pp. 370-386.

Bauer, A.Q.^a ^g , Kraft, A.W.^b , Baxter, G.A.^a , Wright, P.W.^a ^c , Reisman, M.D.^d , Bice, A.R.^a , Park, J.J.^a , Bruchas, M.R.^c ^e ^f , Snyder, A.Z.^a , Lee, J.-M.^a ^b ^c , Culver, J.P.^a ^c ^d

^a Department of Radiology, Washington University School of Medicine, Saint Louis, MO, United States
^b Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
^c Department of Biomedical Engineering, Washington University School of Medicine, Saint Louis, MO, United States
^d Department of Physics, Washington University School of Medicine, Saint Louis, MO, United States
^e Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, United States
^f Department of Neuroscience, Washington University School of Medicine, Saint Louis, MO, United States
^g Washington University School of Medicine, Scott McKinley Research Building, 4515 McKinley Ave, Saint Louis, MO, United States

Abstract
Brain connectomics has expanded from histological assessment of axonal projection connectivity (APC) to encompass resting state functional connectivity (RS-FC). RS-FC analyses are efficient for whole-brain mapping, but attempts to explain aspects of RS-FC (e.g., interhemispheric RS-FC) based on APC have been only partially successful. Neuroimaging with hemoglobin alone lacks specificity for determining how activity in a population of cells contributes to RS-FC. Wide-field mapping of optogenetically defined connectivity could provide insights into the brain’s structure–function relationship. We combined optogenetics with optical intrinsic signal imaging to create an efficient, optogenetic effective connectivity (Opto-EC) mapping assay. We examined EC patterns of excitatory neurons in awake, Thy1-ChR2 transgenic mice. These Thy1-based EC (Thy1-EC) patterns were evaluated against RS-FC over the cortex. Compared to RS-FC, Thy1-EC exhibited increased spatial specificity, reduced interhemispheric connectivity in regions with strong RS-FC, and appreciable connection strength asymmetry. Comparing the topography of Thy1-EC and RS-FC patterns to maps of APC revealed that Thy1-EC more closely resembled APC than did RS-FC. The more general method of Opto-EC mapping with hemoglobin can be determined for 100 sites in single animals in under an hour, and is amenable to other neuroimaging modalities. Opto-EC mapping represents a powerful strategy for examining evolving connectivity-related circuit plasticity. © The Author 2017.

Author Keywords
Cell-specific connectivity; Effective connectivity; Functional neuroimaging; Optical imaging; Optogenetics; Resting state functional connectivity; Structural connectivity

Document Type: Article
Source: Scopus

"Do Changes in Sensory Processing Precede Low Back Pain Development in Healthy Individuals?" (2018) Clinical Journal of Pain

Do Changes in Sensory Processing Precede Low Back Pain Development in Healthy Individuals?
(2018) Clinical Journal of Pain, 34 (6), pp. 525-531.

Hwang, C.-T.^a , Van Dillen, L.R.^a , Haroutounian, S.^b

^a Program in Physical Therapy, Division of Clinical and Translational Research, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
^b Department of Anesthesiology, Division of Clinical and Translational Research, Washington University in St. Louis, School of Medicine, 660 S. Euclid Avenue, Saint Louis, MO, United States

Abstract
Objectives: Low back pain (LBP) is the most commonly reported chronic pain condition. In this study, a clinically relevant, induced- LBP paradigm was used to study sensory processing as a risk factor and predictor for LBP development in healthy people. Our aim was to examine sensory processing in those who do develop LBP and those who do not develop LBP with the paradigm, and to examine the relationships between scores on psychosocial questionnaires and sensory processing measures in these healthy people. Methods: A total of 71 participants completed the Pain Catastrophizing Scale (PCS) and Hospital Anxiety and Depression Scale (HADS) and then took part in quantitative sensory testing. An induced-LBP paradigm, where participants stand for 2 hours and rate their low back symptoms over time, was used to classify participants as those who did develop LBP and those who did not develop LBP. Results: No differences in sensory processing were identified between those who did develop LBP and those who did not develop LBP (Ps>0.05). Scores for the PCS and HADS were similar between the groups (Ps>0.05). Small significant relationships between PCS scores and cold detection and cold pain thresholds were found (rs=0.23 to 0.31; Ps<0.05) and between the pressure pain thresholds at the thenar eminence and paraspinals (r=0.53; P<0.01). Discussion: These results provide evidence that altered sensory processing was not present in healthy people and thus is not a risk factor for development of LBP in standing. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Author Keywords
Inducedpain paradigm; Low back pain; Prolonged standing; Quantitative sensory testing

Document Type: Article
Source: Scopus

"Guanylate cyclase–activating protein 2 contributes to phototransduction and light adaptation in mouse cone photoreceptors" (2018) Journal of Biological Chemistry

Guanylate cyclase–activating protein 2 contributes to phototransduction and light adaptation in mouse cone photoreceptors
(2018) Journal of Biological Chemistry, 293 (19), pp. 7457-7465.

Vinberg, F.^a ^d , Peshenko, I.V.^b , Chen, J.^c , Dizhoor, A.M.^b , Kefalov, V.J.^a ^e

^a Ophthalmology and Visual Sciences, Washington University, School of Medicine, St. Louis, MO, United States
^b Pennsylvania College of Optometry, Salus University, Elkins Park, PA, United States
^c Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA, United States
^d John A. Moran Eye Center, University of Utah, Salt Lake City, UT, United States
^e Dept. of Ophthalmology and Visual Sciences, Washington University in St. Louis, 660 South Euclid Ave., St. Louis, MO, United States

Abstract
Light adaptation of photoreceptor cells is mediated by Ca2dependent mechanisms. In darkness, Ca2 influx through cGMP-gated channels into the outer segment of photoreceptors is balanced by Ca2 extrusion via Na/Ca2, K exchangers (NCKXs). Light activates a G protein signaling cascade, which closes cGMP-gated channels and decreases Ca2 levels in photoreceptor outer segment because of continuing Ca2 extrusion by NCKXs. Guanylate cyclase–activating proteins (GCAPs) then up-regulate cGMP synthesis by activating retinal membrane guanylate cyclases (RetGCs) in low Ca2. This activation of RetGC accelerates photoresponse recovery and critically contributes to light adaptation of the nighttime rod and daytime cone photoreceptors. In mouse rod photoreceptors, GCAP1 and GCAP2 both contribute to the Ca2-feedback mechanism. In contrast, only GCAP1 appears to modulate RetGC activity in mouse cones because evidence of GCAP2 expression in cones is lacking. Surprisingly, we found that GCAP2 is expressed in cones and can regulate light sensitivity and response kinetics as well as light adaptation of GCAP1-deficient mouse cones. Furthermore, we show that GCAP2 promotes cGMP synthesis and cGMP-gated channel opening in mouse cones exposed to low Ca2. Our biochemical model and experiments indicate that GCAP2 significantly contributes to the activation of RetGC1 at low Ca2 when GCAP1 is not present. Of note, in WT mouse cones, GCAP1 dominates the regulation of cGMP synthesis. We conclude that, under normal physiological conditions, GCAP1 dominates the regulation of cGMP synthesis in mouse cones, but if its function becomes compromised, GCAP2 contributes to the regulation of phototransduction and light adaptation of cones. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Document Type: Article
Source: Scopus

"Vancomycin Concentrations in Paraspinal Muscles During Posterior Spinal Fusions for Neuromuscular Scoliosis" (2018) Spine Deformity

Vancomycin Concentrations in Paraspinal Muscles During Posterior Spinal Fusions for Neuromuscular Scoliosis
(2018) Spine Deformity, . Article in Press.

Gregory, J.R.^a , Smith, J.C.^b , Brown-Riley, S.M.^b , Elward, A.M.^b , Luhmann, S.J.^b

^a University of Oklahoma Health Sciences Center, 1100 N Lindsay Ave, Oklahoma City, OK, United States
^b Washington University School of Medicine, 660 S Euclid Ave, St. Louis, MO, United States

Abstract
Study Design: Prospective consecutively enrolled cohort. Objectives: To evaluate paraspinal muscle concentration of intravenously administered vancomycin, at predetermined time points, during posterior spinal fusion (PSF) with instrumentation in neuromuscular scoliosis (NMS). Surgical site infection (SSI) after PSF for NMS can be a devastating complication, which may lead to prolonged antibiotic use, multiple additional surgical procedures, pseudarthroses, and sepsis. Because of significant morbidity of SSIs in NMS, the prophylactic use of vancomycin has been adopted at our institution as standard wound prophylaxis, despite any high-level evidence of its efficacy. Methods: A prospective study of 20 patients who underwent definitive PSF for NMS and received vancomycin infusion preoperatively per institutional protocol. Serum levels were obtained immediately after infusion, at surgical incision, and then at 1, 2, and 4 hours post incision. Muscle tissue samples were simultaneously obtained at incision and at 1, 2, and 4 hours post incision. Samples were analyzed by a validated liquid chromatography–tandem mass spectrometry method. Results: 10 males and 10 females with a mean age of 14+11 years (9–20 years) received a mean infusion of 15.0 mg/kg vancomycin. Mean serum levels were 26.7 μg/mL after infusion, 18.1 at incision, 13.2 at 1 hour, 11.8 at 2 hours, and 7.6 at 4 hours post infusion. Mean muscle levels were 0.5 μg/mL at incision, 0.6 at 1 hour, 0.5 at 2 hours, and 0.7 at 4 hours post infusion. Mean serum levels reached minimum inhibitory concentration (MIC) for Staphylococcus aureus at incision and at all timepoints during surgery. Mean muscle vancomycin levels never reached MIC. No patients had any cardiac or kidney disease, and all patients had normal kidney function according to their preoperative laboratory values. Conclusions: Using accepted guidelines for the administration of intravenous vancomycin preoperatively, serum levels reached MIC at incision and at all timepoints tested during PSF for neuromuscular scoliosis. At no timepoint tested did muscle levels reach MIC. Level of Evidence: Level II. © 2018 Scoliosis Research Society

Author Keywords
Neuromuscular; Paraspinal; Scoliosis; Spinal fusions; Vancomycin

Document Type: Article in Press
Source: Scopus

"Disease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration" (2018) Cell

Disease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration
(2018) Cell, 173 (5), pp. 1073-1081.

Deczkowska, A.^a , Keren-Shaul, H.^a ^b , Weiner, A.^a , Colonna, M.^c , Schwartz, M.^d , Amit, I.^a

^a Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
^b Life Science Core Facility, Weizmann Institute of Science, Rehovot, Israel
^c Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel

Abstract
A major challenge in the field of neurodegenerative diseases and brain aging is to identify the body’s intrinsic mechanism that could sense the central nervous system (CNS) damage early and protect the brain from neurodegeneration. Accumulating evidence suggests that disease-associated microglia (DAM), a recently identified subset of CNS resident macrophages found at sites of neurodegeneration, might play such a protective role. Here, we propose that microglia are endowed with a dedicated sensory mechanism, which includes the Trem2 signaling pathway, to detect damage within the CNS in the form of neurodegeneration-associated molecular patterns (NAMPs). Combining data from transcriptional analysis of DAM at single-cell level and from human genome-wide association studies (GWASs), we discuss potential function of different DAM pathways in the diseased brain and outline how manipulating DAM may create new therapeutic opportunities. Recent analyses of CNS immune cells in neurodegenerative conditions have identified a subset of microglia showing a unique transcriptional and functional signature, disease-associated microglia (DAM). This perspective proposes a role for DAM as a sensor of early CNS damage and discusses the therapeutic potential of modulating DAM function in CNS diseases. © 2018 Elsevier Inc.

Document Type: Review
Source: Scopus

"Depression in patients with coronary artery disease: A more significant problem than previously recognized?" (2017) European Heart Journal – Quality of Care and Clinical Outcomes

Depression in patients with coronary artery disease: A more significant problem than previously recognized?
(2017) European Heart Journal – Quality of Care and Clinical Outcomes, 3 (4), pp. 262-263.

Carney, R.M., Freedland, K.E.

Department of Psychiatry, Washington University School of Medicine, 4320 Forest Park Ave., St. Louis, MO, United States

Document Type: Editorial
Source: Scopus

"Neuregulin signaling pathway in smoking behavior" (2017) Translational psychiatry

Neuregulin signaling pathway in smoking behavior
(2017) Translational psychiatry, 7 (8), p. e1212.

Gupta, R.^a , Qaiser, B.^a , He, L.^b ^c , Hiekkalinna, T.S.^a ^d , Zheutlin, A.B.^e , Therman, S.^d , Ollikainen, M.^a ^f , Ripatti, S.^a ^f , Perola, M.^d , Salomaa, V.^d , Milani, L.^g , Cannon, T.D.^e , Madden, P.A.F.^h , Korhonen, T.^a ^d ^f ⁱ , Kaprio, J.^a ^f , Loukola, A.^a

^a Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
^b Broad Institute of MIT and Harvard, Cambridge, MA, USA
^c Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge, MA, USA
^d National Institute for Health and Welfare, Helsinki, Finland
^e Department of Psychology, Yale University, New Haven, CT, USA
^f Department of Public Health, University of Helsinki, Helsinki, Finland
^g Estonian Genome Center, University of Tartu, Tartu, Estonia
^h Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA
ⁱ Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland

Abstract
Understanding molecular processes that link comorbid traits such as addictions and mental disorders can provide novel therapeutic targets. Neuregulin signaling pathway (NSP) has previously been implicated in schizophrenia, a neurodevelopmental disorder with high comorbidity to smoking. Using a Finnish twin family sample, we have previously detected association between nicotine dependence and ERBB4 (a neuregulin receptor), and linkage for smoking initiation at the ERBB4 locus on 2q33. Further, Neuregulin3 has recently been shown to associate with nicotine withdrawal in a behavioral mouse model. In this study, we scrutinized association and linkage between 15 036 common, low frequency and rare genetic variants in 10 NSP genes and phenotypes encompassing smoking and alcohol use. Using the Finnish twin family sample (N=1998 from 740 families), we detected 66 variants (representing 23 LD blocks) significantly associated (false discovery rate P<0.05) with smoking initiation, nicotine dependence and nicotine withdrawal. We comprehensively annotated the associated variants using expression (eQTL) and methylation quantitative trait loci (meQTL) analyses in a Finnish population sample. Among the 66 variants, we identified 25 eQTLs (in NRG1 and ERBB4), 22 meQTLs (in NRG3, ERBB4 and PSENEN), a missense variant in NRG1 (rs113317778) and a splicing disruption variant in ERBB4 (rs13385826). Majority of the QTLs in blood were replicated in silico using publicly available databases, with additional QTLs observed in brain. In conclusion, our results support the involvement of NSP in smoking behavior but not in alcohol use and abuse, and disclose functional potential for 56 of the 66 associated single-nucleotide polymorphism.

Document Type: Article
Source: Scopus