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WashU weekly Neuroscience publications

“Alzheimer Disease: An Update on Pathobiology and Treatment Strategies” (2019) Cell

Alzheimer Disease: An Update on Pathobiology and Treatment Strategies
(2019) Cell, 179 (2), pp. 312-339. 

Long, J.M., Holtzman, D.M.

Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Long & Holtzman provide a comprehensive overview of the molecules, cells, and mechanisms of Alzheimer disease pathobiology and therapeutic strategies, critically discussing failed strategies and offering a path forward. © 2019 Elsevier Inc.

Alzheimer disease (AD) is a heterogeneous disease with a complex pathobiology. The presence of extracellular β-amyloid deposition as neuritic plaques and intracellular accumulation of hyperphosphorylated tau as neurofibrillary tangles remains the primary neuropathologic criteria for AD diagnosis. However, a number of recent fundamental discoveries highlight important pathological roles for other critical cellular and molecular processes. Despite this, no disease-modifying treatment currently exists, and numerous phase 3 clinical trials have failed to demonstrate benefits. Here, we review recent advances in our understanding of AD pathobiology and discuss current treatment strategies, highlighting recent clinical trials and opportunities for developing future disease-modifying therapies. © 2019 Elsevier Inc.

Document Type: Review
Publication Stage: Final
Source: Scopus

“Effect of a Novel Transition Program on Disability After Stroke: A Trial Protocol” (2019) JAMA Network Open

Effect of a Novel Transition Program on Disability After Stroke: A Trial Protocol
(2019) JAMA Network Open, 2 (10), p. e1912356. 

Somerville, E., Minor, B., Keglovits, M., Yan, Y., Stark, S.

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

Abstract
Importance: A gap in care for stroke survivors exists at the point of transition from inpatient rehabilitation to home, when survivors encounter new environmental barriers because of the cognitive and sensorimotor sequelae of stroke. Resolving these barriers and improving independence in the community have the potential to significantly improve stroke survivors’ long-term morbidity. Objective: To investigate the efficacy and safety of a novel enhanced rehabilitation transition program to reduce environmental barriers and improve daily activity performance and community participation among stroke survivors. Design, Setting, and Participants: This is a phase 2b, single-blind, parallel-group, randomized clinical trial. Participants will be randomized using a 1:1 allocation ratio, stratified by Functional Independence Measure and age, to either attentional control or the intervention. Community Participation Transition After Stroke (COMPASS) is a complex intervention that uses 2 complementary evidence-based interventions: home modifications and strategy training delivered in the home. Community participation after stroke, measured by the Reintegration to Normal Living Index, is the primary outcome. Secondary outcomes include quality of life after stroke, measured by the Stroke Impact Scale, and daily activity performance and magnitude of environmental barriers in the home, both measured by the In-Home Occupational Performance Evaluation. An intention-to-treat analysis will be used. A total of 180 participants, who are 50 years or older, were independent in activities of daily living prior to stroke, and are undergoing inpatient rehabilitation following stroke with a plan to be discharged home, will be included in the study. Discussion: Stroke is a leading cause of serious long-term disability in the United States. The COMPASS study is ongoing. To date, 99 participants have been recruited and 77 randomized, with 37 in the treatment group and 40 in the control group. Resumption of previous activities immediately after discharge can improve immediate and long-term community participation. Results from this study will fill a critical gap in stroke rehabilitation evidence by providing important information about the long-term community participation and daily activity performance among stroke survivors as well as environmental barriers in their homes. Trial Registration: ClinicalTrials.gov identifier: NCT03485820.

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

“The microbiome: A target for Alzheimer disease?” (2019) Cell Research

The microbiome: A target for Alzheimer disease?
(2019) Cell Research, 29 (10), pp. 779-780. 

Seo, D.-O., Boros, B.D., Holtzman, D.M.

Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, 63110, USA

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

“Health Care Professionals’ Perceptions about Sensory-Based Interventions in the NICU” (2019) American Journal of Perinatology

Health Care Professionals’ Perceptions about Sensory-Based Interventions in the NICU
(2019) American Journal of Perinatology, 36 (12), pp. 1229-1236. 

Pineda, R.a b , Roussin, J.a , Heiny, E.a , Smith, J.c

a Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States
b Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
c Department of Quality, Safety and Practice Excellence, Saint Louis Children’s Hospital, St. Louis, MO, United States

Abstract
OBJECTIVE:  The main objective of this article is to define perceptions of health care professionals regarding current use of sensory-based interventions in the neonatal intensive care unit (NICU). STUDY DESIGN:  A multidisciplinary group of NICU health care professionals (n = 108) defined the types of sensory-based interventions used in their NICU, the postmenstrual age (PMA) sensory-based interventions are administered, conditions under which sensory-based interventions are used, and personnel who administer sensory-based interventions. RESULTS:  The most commonly reported tactile intervention was infant holding (88% of respondents), the most common auditory intervention was recorded music/singing (69% of respondents), the most common kinesthetic intervention was occupational and physical therapy (85% of respondents), and the most common vestibular intervention was infant swings (86% of respondents). Tactile interventions were initiated most often at 24 to 26 weeks PMA (74% of respondents), auditory interventions at 30 to 32 weeks (60% of respondents), kinesthetic interventions at 30 to 32 weeks (76% of respondents), vestibular interventions at 33 to 34 weeks (86% of respondents), and visual interventions at 32 to 36 weeks (72% of respondents). Conditions under which sensory-based interventions were administered, and personnel who provided them, varied across settings. CONCLUSION:  Varied use of sensory-based interventions in the NICU were reported. While this study was limited by biased sampling and the identification of health care professionals’ perceptions but not real-world practice, this information can be used to build a comprehensive approach to positive sensory exposures in the NICU. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Document Type: Article
Publication Stage: Final
Source: Scopus

“ER-lysosome contacts enable cholesterol sensing by mTORC1 and drive aberrant growth signalling in Niemann-Pick type C” (2019) Nature Cell Biology

ER-lysosome contacts enable cholesterol sensing by mTORC1 and drive aberrant growth signalling in Niemann-Pick type C
(2019) Nature Cell Biology, 21 (10), pp. 1206-1218. 

Lim, C.-Y.a b , Davis, O.B.a b , Shin, H.R.a b , Zhang, J.a b , Berdan, C.A.a c , Jiang, X.d , Counihan, J.L.a c , Ory, D.S.d , Nomura, D.K.a c , Zoncu, R.a b

a Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
b The Paul F. Glenn Center for Aging Research, University of California, Berkeley, Berkeley, CA, USA
c Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, USA
d Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO, USA

Abstract
Cholesterol activates the master growth regulator, mTORC1 kinase, by promoting its recruitment to the surface of lysosomes by the Rag guanosine triphosphatases (GTPases). The mechanisms that regulate lysosomal cholesterol content to enable mTORC1 signalling are unknown. Here, we show that oxysterol binding protein (OSBP) and its anchors at the endoplasmic reticulum (ER), VAPA and VAPB, deliver cholesterol across ER-lysosome contacts to activate mTORC1. In cells lacking OSBP, but not other VAP-interacting cholesterol carriers, the recruitment of mTORC1 by the Rag GTPases is inhibited owing to impaired transport of cholesterol to lysosomes. By contrast, OSBP-mediated cholesterol trafficking drives constitutive mTORC1 activation in a disease model caused by the loss of the lysosomal cholesterol transporter, Niemann-Pick C1 (NPC1). Chemical and genetic inactivation of OSBP suppresses aberrant mTORC1 signalling and restores autophagic function in cellular models of Niemann-Pick type C (NPC). Thus, ER-lysosome contacts are signalling hubs that enable cholesterol sensing by mTORC1, and targeting the sterol-transfer activity of these signalling hubs could be beneficial in patients with NPC.

Document Type: Article
Publication Stage: Final
Source: Scopus

“ABCC9-related Intellectual disability Myopathy Syndrome is a KATP channelopathy with loss-of-function mutations in ABCC9” (2019) Nature Communications

ABCC9-related Intellectual disability Myopathy Syndrome is a KATP channelopathy with loss-of-function mutations in ABCC9
(2019) Nature Communications, 10 (1), p. 4457. 

Smeland, M.F.a , McClenaghan, C.b , Roessler, H.I.c , Savelberg, S.c , Hansen, G.ÅM.a , Hjellnes, H.a , Arntzen, K.A.d e f , Müller, K.I.d e , Dybesland, A.R.f g , Harter, T.b , Sala-Rabanal, M.b h , Emfinger, C.H.b , Huang, Y.b i , Singareddy, S.S.b , Gunn, J.j , Wozniak, D.F.j , Kovacs, A.k , Massink, M.c , Tessadori, F.c l , Kamel, S.M.l , Bakkers, J.l m , Remedi, M.S.n , Van Ghelue, M.a o , Nichols, C.G.b , van Haaften, G.p

a Department of Medical Genetics, University Hospital of North Norway, Tromsø9019, Norway
b Department of Cell Biology and Physiology, and Center for the Investigation of Membrane Excitability Diseases (CIMED), Washington University, St Louis, MO, 63110, USA
c Department of Genetics, Center for Molecular Medicine, University Medical Center UtrechtUtrecht 3584 CX, Netherlands
d Department of Neurology, University Hospital of North Norway, Tromsø9019, Norway
e Department of Clinical Medicine, UiT-The Arctic University of Norway, Tromsø9019, Norway
f National Neuromuscular Centre of Norway, University Hospital of North Norway, Tromsø9019, Norway
g Department of Physiotherapy, University Hospital of North Norway, Tromsø9019, Norway
h Department of Anesthesiology, Washington University, St Louis, MO, 63110, USA
i Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
j Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA
k Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
l Utrecht 3584 CT, Netherlands
m Department of Medical Physiology, Division of Heart and Lungs, University Medical Center UtrechtUtrecht 3584 CX, Netherlands
n Department of Medicine, Division of Endocrinology, Metabolism and Lipid Research, Washington University, St Louis, MO, 63110, USA
o Department of Medical Genetics, Arctic University of Norway, Tromsø9019, Norway
p Department of Genetics, Center for Molecular Medicine, University Medical Center UtrechtUtrecht 3584 CX, Netherlands

Abstract
Mutations in genes encoding KATP channel subunits have been reported for pancreatic disorders and Cantú syndrome. Here, we report a syndrome in six patients from two families with a consistent phenotype of mild intellectual disability, similar facies, myopathy, and cerebral white matter hyperintensities, with cardiac systolic dysfunction present in the two oldest patients. Patients are homozygous for a splice-site mutation in ABCC9 (c.1320 + 1 G > A), which encodes the sulfonylurea receptor 2 (SUR2) subunit of KATP channels. This mutation results in an in-frame deletion of exon 8, which results in non-functional KATP channels in recombinant assays. SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice, and reduced activity, cardiac dysfunction and ventricular enlargement in zebrafish. We term this channelopathy resulting from loss-of-function of SUR2-containing KATP channels ABCC9-related Intellectual disability Myopathy Syndrome (AIMS). The phenotype differs from Cantú syndrome, which is caused by gain-of-function ABCC9 mutations, reflecting the opposing consequences of KATP loss- versus gain-of-function.

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

“Association Between Severe Maternal Morbidity and Psychiatric Illness Within 1 Year of Hospital Discharge After Delivery” (2019) Obstetrics and Gynecology

Association Between Severe Maternal Morbidity and Psychiatric Illness Within 1 Year of Hospital Discharge After Delivery
(2019) Obstetrics and Gynecology, 134 (4), pp. 695-707. 

Lewkowitz, A.K., Rosenbloom, J.I., Keller, M., López, J.D., Macones, G.A., Olsen, M.A., Cahill, A.G.

Department of Obstetrics and Gynecology, Center for Administrative Data Research, Department of Medicine, the Department of Surgery, Washington University in St. Louis, St. Louis, MO, United States

Abstract
OBJECTIVE: To estimate whether severe maternal morbidity is associated with increased risk of psychiatric illness in the year after delivery hospital discharge. METHODS: This retrospective cohort study used International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes within Florida’s Healthcare Cost and Utilization Project’s databases. The first liveborn singleton delivery from 2005 to 2015 was included; women with ICD-9-CM codes for psychiatric illness or substance use disorder during pregnancy were excluded. The exposure was ICD-9-CM codes during delivery hospitalization of severe maternal morbidity, as per the Centers for Disease Control and Prevention. The primary outcome was ICD-9-CM codes in emergency department encounter or inpatient admission within 1 year of hospital discharge of composite psychiatric morbidity (suicide attempt, depression, anxiety, posttraumatic stress disorder, psychosis, acute stress reaction, or adjustment disorder). The secondary outcome was a composite of ICD-9-CM codes for substance use disorder. We compared women with severe maternal morbidity with those without severe maternal morbidity using multivariable logistic regression adjusting for sociodemographic factors and medical comorbidities. Cox proportional hazard models identified the highest risk period after hospital discharge for the primary outcome. RESULTS: A total of 15,510 women with severe maternal morbidity and 1,178,458 without severe maternal morbidity were included. Within 1 year of hospital discharge, 2.9% (n=452) of women with severe maternal morbidity had the primary outcome compared with 1.6% (n=19,279) of women without severe maternal morbidity, resulting in an adjusted odds ratio (aOR) 1.74 (95% CI 1.58-1.91). The highest risk interval was within 4 months of discharge (adjusted hazard ratio [adjusted HR] 2.53 [95% CI 2.05-3.12]). Most severe maternal morbidity conditions were associated with higher risk of postpartum psychiatric illness. Women with severe maternal morbidity had nearly twofold higher risk of postpartum substance use disorder (170 [1.1%] vs 6,861 [0.6%]; aOR 1.91 [95% CI 1.64-2.23]). CONCLUSION: Though absolute numbers were modest, severe maternal morbidity was associated with increased risk of severe postpartum psychiatric morbidity and substance use disorder. The highest period of risk extended to 4 months after hospital discharge.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Head Motion Predicts Transient Loss of Consciousness in Human Head Trauma: A Case-Control Study of Mixed Martial Artists” (2019) American Journal of Physical Medicine & Rehabilitation

Head Motion Predicts Transient Loss of Consciousness in Human Head Trauma: A Case-Control Study of Mixed Martial Artists
(2019) American Journal of Physical Medicine & Rehabilitation, 98 (10), pp. 859-865. 

Fogarty, A.E., Guay, C.S., Simoneau, G., Colorado, B.S., Segal, G.R., Werner, J.K., Jr, Ellenbogen, J.M.

From the Department of Neurology, Division of Physical Medicine & Rehabilitation, Washington University School of Medicine, St Louis, Missouri (AEF); Department of Anesthesiology, Washington University School of Medicine, St Louis, Missouri (CSG); Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada (GS); Departments of Orthopedic Surgery and Neurology, Division of Physical Medicine & Rehabilitation, Washington University School of Medicine, St Louis, Missouri (BSC); Segal and Lyer Orthodontics, New Jersey (GRS); Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, Maryland (JKWJ, JME); Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (JKWJ); and Behavioral Biology Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland (JME)

Abstract
OBJECTIVE: Concussion with transient loss of consciousness is a commonly observed but poorly understood phenomenon with mounting clinical significance. This study aimed to examine the relationship between head motion in varying planes and transient loss of consciousness in athletes with brain injuries. STUDY DESIGN: A case-control design was used. The Ultimate Fighting Championship database was screened for events ending with knockouts from 2013 to 2016. Time of strike, striking implement, strike location, and head motion were recorded for all knockout strikes (cases) and for a subset of nonknockout strikes (controls). Characteristics of winners and losers were compared using two-tailed t tests. Multivariate logistic regression was used to determine odds ratios for strike characteristics associated with transient loss of consciousness. The Kaplan-Meier estimate was used to describe the temporal distribution of knockouts. RESULTS: One hundred thirty-six fights were identified and 110 videos were included. Head motion in the axial plane was strongly associated with transient loss of consciousness (odds ratio, 45.3; 95% confidence interval, 20.8-98.6). Other predictors of transient loss of consciousness were head motion in sagittal and coronal planes, nonfist striking implements, and strikes to the mandible or maxilla. The Kaplan-Meier survival curve demonstrated a decreasing rate of knockouts through time. CONCLUSIONS: Rotational head acceleration, particularly in the axial plane, is strongly associated with transient loss of consciousness.

Document Type: Article
Publication Stage: Final
Source: Scopus

“PROMIS correlation with NDI and VAS measurements of physical function and pain in surgical patients with cervical disc herniations and radiculopathy” (2019) Journal of Neurosurgery: Spine

PROMIS correlation with NDI and VAS measurements of physical function and pain in surgical patients with cervical disc herniations and radiculopathy
(2019) Journal of Neurosurgery: Spine, 31 (4), pp. 519-524. 

Owen, R.J.a , Khan, A.Z.a , McAnany, S.J.b , Peters, C.a , Zebala, L.P.a

a Washington University in St. Louis, St. Louis, MO, United States
b Hospital for Special Surgery, New York, NY, United States

Abstract
OBJECTIVE The aim of this study was to compare the patient-reported outcome measures Neck Disability Index (NDI) and visual analog scale (VAS) with the Patient Reported Outcomes Measurement Information System (PROMIS) physical function (PF) and pain interference (PI) measures, respectively, and to determine their correlations in a surgical population longitudinally. Legacy outcome measures such as NDI and VAS are essential for analyzing treatments in spine surgery for cervical disc herniations with radiculopathy. Despite their usefulness, administrative burdens impose limits on completion of these measures. PROMIS was developed as a patient outcome measure in order to improve reporting of patient symptoms and function and to reduce administrative burden. Despite early positive results of PROMIS in orthopedics, NDI and VAS scores have not been compared with PROMIS scores in patients with cervical disc herniations with radiculopathy. METHODS Eighty patients undergoing surgery for cervical disc herniations with radiculopathy were included. All patients were treated at the same tertiary spine center. Patients were seen and PROMIS PF and PI, NDI, and VAS arm and neck pain scores were collected preoperatively and at 1 year postoperatively. Correlations between NDI, VAS, and PROMIS PF and PI were quantified using Pearson correlation coefficients. Two-tailed Student t-tests were used to demonstrate correlation significance, with alpha = 0.05. RESULTS All 80 (100%) patients completed all preoperative questionnaires. Fifty-seven (72%) and 75 (94%) patients completed all questionnaires at baseline and at the 6-month and 1-year follow-ups, respectively. PROMIS PF and NDI scores demonstrated a strong negative correlation, with Pearson r values of -0.81, -0.77, and -0.75 at baseline, 6 months, and 1 year. PROMIS PI and VAS neck pain scores demonstrated a moderately positive correlation, with Pearson r values of 0.51, 0.61, and 0.6. PROMIS PI and VAS arm pain scores demonstrated a moderately positive correlation, with Pearson r values of 0.46, 0.47, and 0.45. CONCLUSIONS PROMIS PF scores have a strong negative correlation with NDI scores at baseline and in the post-operative course in patients undergoing surgery for cervical disc herniations with radiculopathy. PROMIS PI scores have a moderately positive correlation with VAS neck and arm pain scores at baseline and in the postoperative course. Surgeons may factor these correlation results into the interpretation of patient-reported outcome measures in patients with cervical radiculopathy. Use of PROMIS PF and PI for this patient population may reduce administrative burden while providing reliable outcomes data. ©AANS 2019, except where prohibited by US copyright law.

Author Keywords
Cervical;  Disc;  Herniation;  Outcomes;  PROMIS;  Radiculopathy

Document Type: Article
Publication Stage: Final
Source: Scopus

“Feasibility of fast brain diffusion MRI to quantify white matter injury in pediatric hydrocephalus” (2019) Journal of Neurosurgery: Pediatrics

Feasibility of fast brain diffusion MRI to quantify white matter injury in pediatric hydrocephalus
(2019) Journal of Neurosurgery: Pediatrics, 24 (4), pp. 461-468. 

Isaacs, A.M.a b , Shimony, J.S.c , Morales, D.M.d , Castaneyra-Ruiz, L.d , Hartman, A.d , Cook, M.d , Smyser, C.D.e , Strahle, J.d , Smyth, M.D.d , Yan, Y.f , McAllister, J.P., IId , McKinstry, R.C.c , Limbrick, D.D., Jr.d

a Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
b Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada
c Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
e Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
f Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States

Abstract
OBJECTIVE Traditionally, diffusion MRI (dMRI) has been performed in parallel with high-resolution conventional MRI, which requires long scan times and may require sedation or general anesthesia in infants and young children. Conversely, fast brain MRI permits image acquisition without the need for sedation, although its short pulse sequences, susceptibility to motion artifact, and contrast resolution have limited its use to assessing ventricular size or major structural variations. Here, the authors demonstrate the feasibility of leveraging a 3-direction fast brain MRI protocol to obtain reliable dMRI measures. METHODS Fast brain MRI with 3-direction dMRI was performed in infants and children before and after hydrocephalus treatment. Regions of interest in the posterior limbs of the internal capsules (PLICs) and the genu of the corpus callosum (gCC) were drawn on diffusion-weighted images, and mean diffusivity (MD) data were extracted. Ventricular size was determined by the frontal occipital horn ratio (FOHR). Differences between and within groups pre- and posttreatment, and FOHR-MD correlations were assessed. RESULTS Of 40 patients who met inclusion criteria (median age 27.5 months), 15 (37.5%), 17 (42.5%), and 8 (20.0%) had posthemorrhagic hydrocephalus (PHH), congenital hydrocephalus (CH), or no intracranial abnormality (controls), respectively. A hydrocephalus group included both PHH and CH patients. Prior to treatment, the FOHR (p < 0.001) and PLIC MD (p = 0.027) were greater in the hydrocephalus group than in the controls. While the mean gCC MD in the hydrocephalus group (1.10 × 10−3 mm2/sec) was higher than that of the control group (0.98), the difference was not significant (p = 0.135). Following a median follow-up duration of 14 months, decreases in FOHR, PLIC MD, and gCC MD were observed in the hydrocephalus group and were similar to those in the control group (p = 0.107, p = 0.702, and p = 0.169, respectively). There were no correlations identified between FOHR and MDs at either time point. CONCLUSIONS The utility of fast brain MRI can be extended beyond anatomical assessments to obtain dMRI measures. A reduction in PLIC and gCC MD to levels similar to those of controls was observed within 14 months following shunt surgery for hydrocephalus in PHH and CH infants. Further studies are required to assess the role of fast brain dMRI for assessing clinical outcomes in pediatric hydrocephalus patients. ©AANS 2019, except where prohibited by US copyright law.

Author Keywords
Diffusion MRI;  Diffusion tensor imaging;  Fast brain MRI;  Hydrocephalus

Document Type: Article
Publication Stage: Final
Source: Scopus

“Genetic ablation of acid ceramidase in Krabbe disease confirms the psychosine hypothesis and identifies a new therapeutic target” (2019) Proceedings of the National Academy of Sciences of the United States of America

Genetic ablation of acid ceramidase in Krabbe disease confirms the psychosine hypothesis and identifies a new therapeutic target
(2019) Proceedings of the National Academy of Sciences of the United States of America, 116 (40), pp. 20097-20103. 

Li, Y.a , Xu, Y.b , Benitez, B.A.a , Nagree, M.S.c , Dearborn, J.T.a , Jiang, X.a , Guzman, M.A.d , Woloszynek, J.C.b , Giaramita, A.b , Yip, B.K.b , Elsbernd, J.b , Babcock, M.C.b , Lo, M.b , Fowler, S.C.e , Wozniak, D.F.f , Vogler, C.A.d , Medin, J.A.c g , Crawford, B.E.b , Sands, M.S.a h

a Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Research, BioMarin Pharmaceutical Inc., Novato, CA 94949, United States
c Department of Medical Biophysics, University of Toronto, Toronto, ON M5S, Canada
d Department of Pathology, St. Louis University School of Medicine, St. Louis, MO 63104, United States
e Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS 66045, United States
f Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
g Pediatrics and Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, United States
h Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Infantile globoid cell leukodystrophy (GLD, Krabbe disease) is a fatal demyelinating disorder caused by a deficiency in the lysosomal enzyme galactosylceramidase (GALC). GALC deficiency leads to the accumulation of the cytotoxic glycolipid, galactosylsphingosine (psychosine). Complementary evidence suggested that psychosine is synthesized via an anabolic pathway. Here, we show instead that psychosine is generated catabolically through the deacylation of galactosylceramide by acid ceramidase (ACDase). This reaction uncouples GALC deficiency from psychosine accumulation, allowing us to test the long-standing “psychosine hypothesis.” We demonstrate that genetic loss of ACDase activity (Farber disease) in the GALC-deficient mouse model of human GLD (twitcher) eliminates psychosine accumulation and cures GLD. These data suggest that ACDase could be a target for substrate reduction therapy (SRT) in Krabbe patients. We show that pharmacological inhibition of ACDase activity with carmofur significantly decreases psychosine accumulation in cells from a Krabbe patient and prolongs the life span of the twitcher (Twi) mouse. Previous SRT experiments in the Twi mouse utilized L-cycloserine, which inhibits an enzyme several steps upstream of psychosine synthesis, thus altering the balance of other important lipids. Drugs that directly inhibit ACDase may have a more acceptable safety profile due to their mechanistic proximity to psychosine biogenesis. In total, these data clarify our understanding of psychosine synthesis, confirm the long-held psychosine hypothesis, and provide the impetus to discover safe and effective inhibitors of ACDase to treat Krabbe disease. © 2019 National Academy of Sciences. All rights reserved.

Author Keywords
Acid ceramidase;  Galactosylceramidase;  Krabbe disease;  Psychosine;  Twitcher mouse

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

“Pacemakers, Deep Brain Stimulators, Cochlear Implants, and Nerve Stimulators: A Review of Common Devices Encountered in the Dermatologic Surgery Patient” (2019) Dermatologic Surgery : Official Publication for American Society for Dermatologic Surgery (et al.)

Pacemakers, Deep Brain Stimulators, Cochlear Implants, and Nerve Stimulators: A Review of Common Devices Encountered in the Dermatologic Surgery Patient
(2019) Dermatologic Surgery : Official Publication for American Society for Dermatologic Surgery [et al.], 45 (10), pp. 1228-1236. 

Tripathi, S.V.a , Hurst, E.A.b

a *All authors are affiliated with the Division of Dermatology, Washington University in St. Louis, St. Louis, MO, United States
b All authors are affiliated with the Division of Dermatology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
BACKGROUND: In dermatologic and procedural surgery settings, there are commonly encountered devices in patients. Safe surgical planning requires familiarity with these devices. OBJECTIVE: To review the current implanted devices in patients and recommendations for surgical planning around these devices. METHODS AND MATERIALS: A comprehensive review using PubMed and published device recommendations was performed, searching for those most relevant to dermatologic surgery. RESULTS: Devices such as pacemakers and implantable cardiac defibrillators, deep brain stimulators, cochlear implants, and various nerve stimulators are potential devices that may be encountered in patients and specific recommendations exist for each of these devices. CONCLUSION: Dermatologic surgeons’ knowledge of implanted devices in patients is paramout to safe surgical procedures.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Riding the Rhythm of Melatonin Through Pregnancy to Deliver on Time” (2019) Frontiers in Endocrinology

Riding the Rhythm of Melatonin Through Pregnancy to Deliver on Time
(2019) Frontiers in Endocrinology, 10, art. no. 616, . 

McCarthy, R.a , Jungheim, E.S.a , Fay, J.C.b , Bates, K.c , Herzog, E.D.c , England, S.K.a

a Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Biology, University of Rochester, Rochester, NY, United States
c Department of Biology, Washington University, St. Louis, MO, United States

Abstract
Pregnancy is influenced by the circadian (“circa” or approximately; diēm or day) system, which coordinates physiology and behavior with predictable daily changes in the environment such as light/dark cycles. For example, most species deliver around a particular time of day. In mammals, circadian rhythms are controlled by the master circadian pacemaker, the suprachiasmatic nucleus. One key way that the suprachiasmatic nucleus coordinates circadian rhythms throughout the body is by regulating production of the sleep-promoting hormone melatonin. Serum melatonin concentration, which peaks at night and is suppressed during the day, is one of the best biological indicators of circadian timing. Circadian misalignment causes maternal disturbances in the temporal organization of many physiological processes including melatonin synthesis, and these disturbances of the circadian system have been linked to an increased risk for pregnancy complications. Here, we review evidence that melatonin helps regulate the maternal and fetal circadian systems and the timing of birth. Finally, we discuss the potential for melatonin-based therapeutic strategies to alleviate poor pregnancy outcomes such as preeclampsia and preterm birth. © Copyright © 2019 McCarthy, Jungheim, Fay, Bates, Herzog and England.

Author Keywords
chronodisruption;  circadian;  fetal outcomes;  gestation;  melatonin;  parturition;  pregnancy

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

“Combined Anti-inflammatory and Neuroprotective Treatments Have the Potential to Impact Disease Phenotypes in Cln3−/− Mice” (2019) Frontiers in Neurology

Combined Anti-inflammatory and Neuroprotective Treatments Have the Potential to Impact Disease Phenotypes in Cln3−/− Mice
(2019) Frontiers in Neurology, 10, art. no. 963, . 

Tarczyluk-Wells, M.A.a g , Salzlechner, C.a , Najafi, A.R.b , Lim, M.J.c d , Smith, D.e , Platt, F.M.e , Williams, B.P.a , Cooper, J.D.a b f

a Department of Basic and Clinical Neuroscience, King’s College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London, United Kingdom
b Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, United States
c Guy’s and St. Thomas’ NHS Foundation Trust, King’s Health Partners Academic Health Science Centre, Evelina London Children’s Hospital, London, United Kingdom
d Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
e Department of Pharmacology, University of Oxford, Oxford, United Kingdom
f Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
g Centre for Brain Research, University of Auckland, Auckland, New Zealand

Abstract
Batten disease, or juvenile NCL, is a fatal neurodegenerative disorder that occurs due to mutations in the CLN3 gene. Because the function of CLN3 remains unclear, experimental therapies for JNCL have largely concentrated upon the targeting of downstream pathomechanisms. Neuron loss is preceded by localized glial activation, and in this proof-of-concept study we have investigated whether targeting this innate immune response with ibuprofen in combination with the neuroprotective agent lamotrigine improves the previously documented beneficial effects of immunosuppressants alone. Drugs were administered daily to symptomatic Cln3−/− mice over a 3 month period, starting at 6 months of age, and their impact was assessed using both behavioral and neuropathological outcome measures. During the treatment period, the combination of ibuprofen and lamotrigine significantly improved the performance of Cln3−/− mice on the vertical pole test, slowing the disease-associated decline, but had less of an impact upon their rotarod performance. There were also moderate and regionally dependent effects upon astrocyte activation that were most pronounced for ibuprofen alone, but there was no overt effect upon microglial activation. Administering such treatments for longer periods will enable testing for any impact upon the neuron loss that occurs later in disease progression. Given the partial efficacy of these treatments, it will be important to test further drugs of this type in order to find more effective combinations. © Copyright © 2019 Tarczyluk-Wells, Salzlechner, Najafi, Lim, Smith, Platt, Williams and Cooper.

Author Keywords
Batten disease;  CLN3 disease;  glial activation;  ibuprofen;  inflammation;  lamotrigine;  neurodegeneration

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

“Application of the Co-Agonist Concerted Transition Model to Analysis of GABAA Receptor Properties” (2019) Current Neuropharmacology

Application of the Co-Agonist Concerted Transition Model to Analysis of GABAA Receptor Properties
(2019) Current Neuropharmacology, 17 (9), pp. 843-851. 

Germann, A.L.a , Steinbach, J.H.a b , Akk, G.a b

a Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
b Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, United States

Abstract
The co-agonist concerted transition model is a simple and practical solution to analyze various aspects of GABAA receptor function. Several model-based predictions have been verified experimentally in previous reports. We review here the practical implications of the model and demonstrate how it enables simplification of the experimental procedure and data analysis to characterize the effects of mutations or properties of novel ligands. Specifically, we show that the value of EC50 and the magnitude of current response are directly affected by basal activity, and that coapplication of a background agonist acting at a distinct site or use of a gain-of-function mutation can be employed to enable studies of weak activators or mutated receptors with impaired gating. We also show that the ability of one GABAergic agent to potentiate the activity elicited by another is a computable value that depends on the level of constitutive activity of the ion channel and the ability of each agonist to directly activate the receptor. Significantly, the model accurately accounts for situations where the paired agonists interact with the same site compared to distinct sites on the receptor. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.

Author Keywords
activation;  agonist;  GABAA receptor;  ion channel;  model;  modulation;  potentiation;  potentiator.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Control networks of the frontal lobes” (2019) Handbook of Clinical Neurology

Control networks of the frontal lobes
(2019) Handbook of Clinical Neurology, 163, pp. 333-347. 

Marek, S.a , Dosenbach, N.U.F.a b c d e

a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States
c Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
d Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
e Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO, United States

Abstract
The human brain is organized into specialized functional brain networks. Some networks are dedicated to early sensory processing, and others to generating motor outputs. Yet, the bulk of the human brain’s functional networks is actually dedicated to control processes. The two control networks most important for the impressive repertoire of control-related behaviors that humans are able to instantiate and maintain are the frontoparietal and cinguloopercular networks. We provide evidence that these two control networks largely contribute to nonoverlapping domains of control. These networks largely have been studied using fMRI, which is sensitive only to infraslow activity. Complementary electrophysiological techniques have provided evidence that these networks manifest at substantially faster frequencies (delta–alpha band), supporting their role in coordination of whole-brain functional network activity. Both the frontoparietal and cinguloopercular networks demonstrate protracted development, supporting increases in control-related performance. Recent studies from our lab indicate these control networks exhibit measurable individual specificity, highlighting the importance of individualized paradigms in neuroimaging studies to advance our understanding of typical and atypical control network function throughout the life span. © 2019 Elsevier B.V.

Author Keywords
Cinguloopercular network;  Control;  Development;  Frontoparietal network;  Functional networks;  Resting state

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

“Connectional gradients underlie functional transitions in monkey pre-supplementary motor area” (2019) Progress in Neurobiology

Connectional gradients underlie functional transitions in monkey pre-supplementary motor area
(2019) Progress in Neurobiology, art. no. 101699, . 

Albertini, D.a , Gerbella, M.a , Lanzilotto, M.a c , Livi, A.a b , Maranesi, M.a , Ferroni, C.G.a , Bonini, L.a

a Department of Medicine and Surgery, University of Parma, via Volturno 39, Parma, 43125, Italy
b Department of Neuroscience, Washington University in St. LouisMO 63110, United States
c Department of Psychology, University of Turin, via Verdi 10, Torino, 10124, Italy

Abstract
The pre-supplementary motor area F6 is involved in a variety of functions in multiple domains, from planning/withholding goal-directed actions in space to rule-based cognitive processes and social interactions. Yet, the neural machinery underlying this functional heterogeneity remains unclear. Here, we measured local population dynamics in different rostro-caudal sites of cytoarchitectonically verified area F6 in two monkeys during spatial, contextual and motor processes, both in individual and social conditions. Then, we correlated multimodal population tuning with local anatomical connectivity revealed by neural tracer injections into the functionally characterized sites. We found stronger tuning for object position relative to the monkey in the rostral portion of area F6 than in its caudal part, which in turn exhibits stronger tuning to self and other’s (observed) action. Functional specificities were associated with a rostro-caudal transition in connectivity strength from lateral prefrontal cortex, pregenual anterior cingulate cortex and associative striatum (rostrally), to dorso-ventral premotor areas and the motor putamen (caudally). These findings suggest that the functional heterogeneity of the pre-supplementary area F6 is accounted for by gradual transitions in functional properties grounded on local cortico-cortical and cortico-striatal connectional specificities. © 2019 The Authors

Author Keywords
Action observation;  Mirror neuron;  motor control;  Neuroanatomy;  Pre-sma

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