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WUSTL Neuroscience Publications Archive - July 2013

Scopus weekly report:

July 19, 2013


July 19, 2013


Mawuenyega, K.G., Kasten, T., Sigurdson, W., Bateman, R.J.
Amyloid-beta isoform metabolism quantitation by stable isotope-labeled kinetics
(2013) Analytical Biochemistry, 440 (1), pp. 56-62. Article in Press. 

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

Abundant evidence suggests a central role for the amyloid-beta (Aβ) peptide in Alzheimer's disease (AD) pathogenesis. Production and clearance of different Aβ isoforms have been established as targets of proposed disease-modifying therapeutic treatments of AD. However, previous studies used multiple sequential purification steps to isolate the isoforms individually and quantitate them based on a common mid-domain peptide. We created a method to simultaneously purify Aβ isoforms and quantitate them by the specific C-terminal peptides in order to investigate Aβ isoform physiology in the central nervous system. By using standards generated from in vitro metabolic labeling, the relative quantitation of four peptides representing total amount of Aβ (Aβ-Total), Aβ38, Aβ40, and Aβ42 were achieved both in cell culture and in human cerebrospinal fluid (CSF). Standard curves for each isoform demonstrated good sensitivity with very low limits of detection and high accuracy. Because the assay does not require antibody development for each Aβ isoform peptide, significant improvements in the throughput and accuracy of isoform quantitation were achieved. © 2013 Elsevier Inc.

Author Keywords
Alzheimer's disease;  Amyloid-beta isoforms;  Cerebrospinal fluid;  Mass spectrometry;  Relative quantitation

Document Type: Article in Press
Source: Scopus

Burke, R.E.a c , O'Malley, K.b
Axon degeneration in Parkinson's disease
(2013) Experimental Neurology, 246, pp. 72-83. Cited 2 times.

a Department of Neurology, Columbia University, 650 W 168th St., New York, NY 10032, United States
b Department of Pathology and Cell Biology, Columbia University, 650 W 168th St., New York, NY 10032, United States
c Department of Anatomy and Neurobiology, Washington University, School of Medicine, 660 S Euclid Ave., Saint Louis, MO 63110-1010, United States

Parkinson's disease (PD) is the most common neurodegenerative disease of the basal ganglia. Like other adult-onset neurodegenerative disorders, it is without a treatment that forestalls its chronic progression. Efforts to develop disease-modifying therapies to date have largely focused on the prevention of degeneration of the neuron soma, with the tacit assumption that such approaches will forestall axon degeneration as well. We herein propose that future efforts to develop neuroprotection for PD may benefit from a shift in focus to the distinct mechanisms that underlie axon degeneration. We review evidence from human post-mortem studies, functional neuroimaging, genetic causes of the disease and neurotoxin models that axon degeneration may be the earliest feature of the disease, and it may therefore be the most appropriate target for early intervention. In addition, we present evidence that the molecular mechanisms of degeneration of axons are separate and distinct from those of neuron soma. Progress is being made in understanding these mechanisms, and they provide possible new targets for therapeutic intervention. We also suggest that the potential for axon re-growth in the adult central nervous system has perhaps been underestimated, and it offers new avenues for neurorestoration. In conclusion, we propose that a new focus on the neurobiology of axons, their molecular pathways of degeneration and growth, will offer novel opportunities for neuroprotection and restoration in the treatment of PD and other neurodegenerative diseases. © 2012 Elsevier Inc.

Author Keywords
α-Synuclein;  Akt;  Autophagy;  LRRK2;  MPTP;  MTor;  Striatum;  Substantia nigra;  WldS

Document Type: Review
Source: Scopus

Chen, Y.a , Williams, S.H.b , McNulty, A.L.c , Hong, J.H.a d , Lee, S.H.a , Rothfusz, N.E.c , Parekh, P.K.a , Moore, C.a , Gereau IV, R.W.h , Taylor, A.B.e f , Wang, F.g , Guilak, F.b , Liedtke, W.a d i
Temporomandibular joint pain: A critical role for Trpv4 in the trigeminal ganglion
(2013) Pain, 154 (8), pp. 1295-1304. 

a Duke University Medical Center, Department of Medicine, Duke Clinics for Pain and Palliative Care, Durham, NC 27710, United States
b Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, United States
c Department of Orthopaedic Surgery, Duke University, Durham, NC, United States
d Duke Clinics for Pain and Palliative Care, Durham, NC, United States
e Department of Community and Family Medicine, Duke University, Durham, NC, United States
f Department of Evolutionary Anthropology, Duke University, Durham, NC, United States
g Department of Cell Biology, Duke University, Durham, NC, United States
h Department of Anesthesiology, Washington University, St. Louis, MO, United States
i Duke Center for Neuroengineering, Durham, NC, United States

Temporomandibular joint disorder (TMJD) is known for its mastication-associated pain. TMJD is medically relevant because of its prevalence, severity, chronicity, the therapy-refractoriness of its pain, and its largely elusive pathogenesis. Against this background, we sought to investigate the pathogenetic contributions of the calcium-permeable TRPV4 ion channel, robustly expressed in the trigeminal ganglion sensory neurons, to TMJ inflammation and pain behavior. We demonstrate here that TRPV4 is critical for TMJ-inflammation-evoked pain behavior in mice and that trigeminal ganglion pronociceptive changes are TRPV4-dependent. As a quantitative metric, bite force was recorded as evidence of masticatory sensitization, in keeping with human translational studies. In Trpv4-/- mice with TMJ inflammation, attenuation of bite force was significantly less than in wildtype (WT) mice. Similar effects were seen with systemic application of a specific TRPV4 inhibitor. TMJ inflammation and mandibular bony changes were apparent after injections of complete Freund adjuvant but were remarkably independent of the Trpv4 genotype. It was intriguing that, as a result of TMJ inflammation, WT mice exhibited significant upregulation of TRPV4 and phosphorylated extracellular-signal-regulated kinase (ERK) in TMJ-innervating trigeminal sensory neurons, which were absent in Trpv4-/- mice. Mice with genetically-impaired MEK/ERK phosphorylation in neurons showed resistance to reduction of bite force similar to that of Trpv4-/- mice. Thus, TRPV4 is necessary for masticatory sensitization in TMJ inflammation and probably functions upstream of MEK/ERK phosphorylation in trigeminal ganglion sensory neurons in vivo. TRPV4 therefore represents a novel pronociceptive target in TMJ inflammation and should be considered a target of interest in human TMJD. © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Author Keywords
Bite force;  ERK activation;  Temporomandibular joint disorder;  Trigeminal ganglion;  Trpv4

Document Type: Article
Source: Scopus

Farasatpour, M.a , Janardhan, R.a , Williams, C.D.a , Margenthaler, J.A.b , Virgo, K.S.c , Johnson, F.E.a d
Breast cancer in patients with schizophrenia
(2013) American Journal of Surgery, . Article in Press. 

a Department of Surgery, Saint Louis University Medical Center, 3635 Vista Avenue, St. Louis, MO 63110-0250, USA
b Department of Surgery, Washington University, St. Louis, MO, USA
c Department of Surgery, American Cancer Society, Atlanta, GA, USA
d Department of Surgery, John Cochran Veterans Affairs Medical Center, St. Louis, MO, USA

Background: Schizophrenia has a powerful impact on the outcomes of treatment for physical disorders. This study sought to estimate how the presence of schizophrenia disrupts the course of diagnosis and initial treatment of breast cancer. Methods: We searched the Patient Treatment File, a comprehensive computer-based system for inpatient data in the Department of Veterans Affairs (DVA) medical system, to identify patients with codes for schizophrenia or schizoaffective disorder who later developed breast cancer. These data were augmented with chart-based clinical data. Results: There were 56 evaluable patients from 34 DVA facilities; 37 (66%) were female. Delay in diagnosis was common. The mean size of the primary tumor was 4 cm in those for whom these data were recorded. Delay in diagnosis was common and many never received the indicated surgery. Distant metastases were present on diagnosis in 12 (21%) and developed after diagnosis in 14 (25%) others, including 7 who inappropriately delayed or refused indicated surgery and 4 who inappropriately delayed or refused indicated neoadjuvant chemotherapy. Twelve verbally abused or physically attacked caregivers. Conclusions: Patients with schizophrenia who later develop breast cancer often deny they have cancer. They often have high-stage disease at diagnosis and often delay or refuse therapy. Breast-conserving multimodality therapy is often not feasible. © 2013 Elsevier Inc. All rights reserved.

Author Keywords
Breast cancer;  Outcomes;  Schizophrenia;  Surgery

Document Type: Article in Press
Source: Scopus

Omizzolo, C.a b , Scratch, S.E.a , Stargatt, R.a b , Kidokoro, H.c , Thompson, D.K.a d , Lee, K.J.a e , Cheong, J.a f g , Neil, J.c , Inder, T.E.a c , Doyle, L.W.a e f g , Anderson, P.J.a c e
Neonatal brain abnormalities and memory and learning outcomes at 7 years in children born very preterm
(2013) Memory, . Article in Press. 

a Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, VIC, Australia
b Department of Psychology, La Trobe University, Bundoora, VIC, Australia
c Department of Pediatrics, Washington University in St Louis Medical School, St Louis, MO, USA
d Centre for Neuroscience, The University of Melbourne, Parkville, VIC, Australia
e Department of Paediatrics, The University of Melbourne, Royal Children's Hospital, Parkville, VIC, Australia
f Royal Women's Hospital, Parkville, VIC, Australia
g Department of Obstetrics and Gynaecology, The University of Melbourne, Royal Women's Hospital, Parkville, VIC, Australia

Using prospective longitudinal data from 198 very preterm and 70 full term children, this study characterised the memory and learning abilities of very preterm children at 7 years of age in both verbal and visual domains. The relationship between the extent of brain abnormalities on neonatal magnetic resonance imaging (MRI) and memory and learning outcomes at 7 years of age in very preterm children was also investigated. Neonatal MRI scans were qualitatively assessed for global, white-matter, cortical grey-matter, deep grey-matter, and cerebellar abnormalities. Very preterm children performed less well on measures of immediate memory, working memory, long-term memory, and learning compared with term-born controls. Neonatal brain abnormalities, and in particular deep grey-matter abnormality, were associated with poorer memory and learning performance at 7 years in very preterm children. Findings support the importance of cerebral neonatal pathology for predicting later memory and learning function. © 2013 Copyright Taylor and Francis Group, LLC.

Author Keywords
Gestational age;  Memory and learning;  Neonatal brain abnormalities;  Very preterm

Document Type: Article in Press
Source: Scopus

Langer, J.K.a , Rodebaugh, T.L.b , Menatti, A.R.b , Weeks, J.W.b , Schneier, F.R.c
Psychometric Properties of the Gaze Anxiety Rating Scale: Convergent, Discriminant, and Factorial Validity
(2013) Cognitive Behaviour Therapy, . Article in Press. 

a Department of Psychology, Washington University in St. Louis, St. Louis, USA
b Department of Psychology, Ohio University, Athens, USA
c Columbia University Medical Center, New York, USA

Fear and avoidance of gaze are two features thought to be associated with problematic social anxiety. Avoidance of eye contact has been linked with such undesirable traits as deceptiveness, insincerity, and lower self-esteem. The Gaze Anxiety Rating Scale (GARS) is a self-report measure designed to assess gaze anxiety and avoidance, but its psychometric properties have only been assessed in one preliminary study. We further investigated psychometric properties of the GARS by assessing convergent and factorial validity. We obtained a two-factor solution: gaze anxiety and avoidance across situations (1) in general (GARS-General) and (2) related to dominance communication (GARS-Dominance). The GARS-General factor related more strongly to social anxiety than the GARS-Dominance, and convergent validity of the factors was supported by expected relationships with personality and social anxiety variables. Our results indicate that the GARS subscales are psychometrically valid measures of gaze aversion, supporting their use in future study of the relationship between social anxiety and eye contact behavior. © 2013 Copyright Swedish Association for Behaviour Therapy.

Author Keywords
dominance;  eye contact;  factor analysis;  Gaze Anxiety Rating Scale;  social anxiety

Document Type: Article in Press
Source: Scopus

Padhye, L.V.a , Van Stavern, G.P.b , Sharma, A.c , Viets, R.c , Huecker, J.B.b , Gordon, M.O.b
Association between visual parameters and neuroimaging features of idiopathic intracranial hypertension
(2013) Journal of the Neurological Sciences, . Article in Press. 

a School of Medicine, Washington University in St. Louis, St. Louis, MO 63108, United States
b Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63108, United States
c Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States

Background/aims: Papilledema refers to optic disc swelling resulting from high intracranial pressure (ICP). The precise mechanism by which papilledema occurs remains uncertain. Although orbital neuroimaging features associated with papilledema are well-described, it is unclear whether these findings correlate with visual function. Idiopathic Intracranial Hypertension (IIH) is a condition in which the intracranial pressure is elevated with no obvious cause, causing papilledema and visual loss. The utility of papilledema and IIH neuroimaging findings as a surrogate marker for visual loss, or a predictor of visual loss, is understudied. This retrospective cross-sectional review aims to correlate parameters of visual function with orbital magnetic resonance imaging (MRI) findings. Methods: Patients meeting criteria for IIH who had received orbital imaging within 4 weeks of examination were included. Visual parameters of papilledema grade, visual field mean deviation, and visual acuity were correlated with neuroimaging features, including optic nerve thickness, and optic nerve sheath thickness, among others. All MRI scans were reviewed by a neuroradiologist blinded to clinical status. Spearman rank correlations and t-tests were generated with SAS (v9.2). Results: Thirty five patients were included. No significant relationships were found between the main visual parameters of papilledema grade and visual field mean deviation, and MRI findings. Conclusions: We found no significant correlation between visual parameters and imaging features of papilledema. This might indicate that MRI features may provide insight into the structural changes that occur in papilledema, but may not be helpful when making clinical management decisions for patients with IIH in particular, and papilledema in general. © 2013 Elsevier B.V. All rights reserved.

Author Keywords
Idiopathic intracranial hypertension;  Neuroimaging;  Optic neuropathy;  Orbital imaging;  Papilledema;  Pseudotumor cerebri

Document Type: Article in Press
Source: Scopus

Bussey, T.J.a , Barch, D.M.b , Baxter, M.G.c
Testing long-term memory in animal models of schizophrenia: Suggestions from CNTRICS
(2013) Neuroscience and Biobehavioral Reviews, . Article in Press. 

a Department of Experimental Psychology and The MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, CB2 3EB, UK
b Department of Psychology, Washington University, St Louis, MO, USA
c Glickenhaus Laboratory of Neuropsychology and Friedman Brain Institute, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA

This paper reports the results of discussions at the fourth meeting of Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) meeting, held over two days in Washington, DC in April 2011. The meeting focused on animal paradigms for assessing the cognitive constructs relevant to schizophrenia identified in previous CNTRICS meetings. This report focuses on the outcome of discussions in the general area of long-term memory. A number of candidate animal paradigms were discussed. Two of these - one for rodents and one for non-human primates - were recommended as particularly promising for further development. © 2013 Elsevier Ltd. All rights reserved.

Author Keywords
Episodic memory;  Hippocampus;  Mouse;  Neuropsychiatric disease;  Object recognition;  Paired-associate learning;  Prefrontal cortex;  Rat;  Relational memory;  Rodent;  Touchscreen

Document Type: Article in Press
Source: Scopus

Shultz, S.R.a , Cardamone, L.a , Liu, Y.R.a , Edward Hogan, R.b , MacCotta, L.b , Wright, D.K.c , Zheng, P.a , Koe, A.a , Gregoire, M.-C.d , Williams, J.P.c , Hicks, R.J.e , Jones, N.C.a , Myers, D.E.a , O'Brien, T.J.a , Bouilleret, V.a f
Can structural or functional changes following traumatic brain injury in the rat predict epileptic outcome?
(2013) Epilepsia, 54 (7), pp. 1240-1250. 

a Department of Medicine (RMH), University of Melbourne Victoria, Clinical Sciences Building, Royal Parade, Parkville, VIC 3050, Australia
b Department of Neurology, Washington University, St. Louis, MO, United States
c Small Animal MRI Facility, Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
d Australian Nuclear Science and Technology Organization, Kirrawee, NSW, Australia
e Centre for Molecular Imaging, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
f Department of Neurophysiology and Epilepsy, APHP CHU Bicetre, Paris, France

Purpose Posttraumatic epilepsy (PTE) occurs in a proportion of traumatic brain injury (TBI) cases, significantly compounding the disability, and risk of injury and death for sufferers. To date, predictive biomarkers for PTE have not been identified. This study used the lateral fluid percussion injury (LFPI) rat model of TBI to investigate whether structural, functional, and behavioral changes post-TBI relate to the later development of PTE. Methods Adult male Wistar rats underwent LFPI or sham injury. Serial magnetic resonance (MR) and positron emission tomography (PET) imaging, and behavioral analyses were performed over 6 months postinjury. Rats were then implanted with recording electrodes and monitored for two consecutive weeks using video- electroencephalography (EEG) to assess for PTE. Of the LFPI rats, 52% (n = 12) displayed spontaneous recurring seizures and/or epileptic discharges on the video-EEG recordings. Key Findings MRI volumetric and signal analysis of changes in cortex, hippocampus, thalamus, and amygdala, 18F- fluorodeoxyglucose (FDG)-PET analysis of metabolic function, and behavioral analysis of cognitive and emotional changes, at 1 week, and 1, 3, and 6 months post-LFPI, all failed to identify significant differences on univariate analysis between the epileptic and nonepileptic groups. However, hippocampal surface shape analysis using large-deformation high-dimensional mapping identified significant changes in the ipsilateral hippocampus at 1 week postinjury relative to baseline that differed between rats that would go onto become epileptic versus those who did not. Furthermore, a multivariate logistic regression model that incorporated the 1 week, and 1 and 3 month 18F-FDG PET parameters from the ipsilateral hippocampus was able to correctly predict the epileptic outcome in all of the LFPI cases. As such, these subtle changes in the ipsilateral hippocampus at acute phases after LFPI may be related to PTE and require further examination. Significance These findings suggest that PTE may be independent of major structural, functional, and behavioral changes induced by TBI, and suggest that more subtle abnormalities are likely involved. However, there are limitations associated with studying acquired epilepsies in animal models that must be considered when interpreting these results, in particular the failure to detect differences between the groups may be related to the limitations of properly identifying/separating the epileptic and nonepileptic animals into the correct group. © 2013 Wiley Periodicals, Inc.

Author Keywords
Epileptogenesis;  Lateral fluid percussion injury;  MRI;  PET;  Posttraumatic epilepsy

Document Type: Article
Source: Scopus

Slattery, E., White, A.J., Gauthier, M., Linscott, L., Hirose, K.
Tolosa-Hunt syndrome masquerading as Gradenigo syndrome in a teenager
(2013) International Journal of Pediatric Otorhinolaryngology, 77 (7), pp. 1219-1221. 

Departments of Otolaryngology, Radiology and Pediatrics, Washington University, 660 South Euclid Avenue, Campus Box 8115, St. Louis MO 63110, United States

Tolosa-Hunt syndrome is an idiopathic chronic granulomatous inflammatory process commonly involving the cavernous sinus and the orbit [1]. Symptoms include unilateral eye pain, ophthalmoplegia, headache, and facial pain in the distribution of the upper divisions of the trigeminal nerve and are highly responsive to steroid therapy. Gradenigo syndrome describes extension of a middle ear infection to the petrous apex, with trigeminal pain and ophthalmoplegia, typically responsive to antibiotics and often surgical drainage. We report a case of a 17 year-old girl with apparent Gradenigo syndrome, presenting with unilateral eye pain, abducens palsy, headache, hearing loss and serous otitis media, who was ultimately diagnosed with Tolosa-Hunt syndrome. © 2013 Elsevier Ireland Ltd.

Author Keywords
Gradenigo;  Ophthalmoplegia;  Otitis media;  Tolosa-Hunt

Document Type: Article
Source: Scopus