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WUSTL Neuroscience Publications Archive - December 2015

December 2015

December 28, 2015

Bogdan R.a b , Pagliaccio D.c , Baranger D.A.A.a b , Hariri A.R.c
Genetic moderation of stress effects on corticolimbic circuitry
(2016) Neuropsychopharmacology, 41 (1), pp. 275-296. Cited 1 time.

DOI: 10.1038/npp.2015.216

a Department of Psychology, BRAIN Lab, Washington University in St Louis, WUSTL CB 1125, One Brookings Drive, St Louis, MO, United States
b Neurosciences Program, Division of Biology and Biomedical Sciences, Washington University in St Louis, St Louis, MO, United States
c Department of Psychology and Neuroscience, Laboratory of NeuroGenetics, Duke University, Durham, NC, United States

Stress exposure is associated with individual differences in corticolimbic structure and function that often mirror patterns observed in psychopathology. Gene x environment interaction research suggests that genetic variation moderates the impact of stress on risk for psychopathology. On the basis of these findings, imaging genetics, which attempts to link variability in DNA sequence and structure to neural phenotypes, has begun to incorporate measures of the environment. This research paradigm, known as imaging gene x environment interaction (iGxE), is beginning to contribute to our understanding of the neural mechanisms through which genetic variation and stress increase psychopathology risk. Although awaiting replication, evidence suggests that genetic variation within the canonical neuroendocrine stress hormone system, the hypothalamic-pituitary-adrenal axis, contributes to variability in stress-related corticolimbic structure and function, which, in turn, confers risk for psychopathology. For iGxE research to reach its full potential it will have to address many challenges, of which we discuss: (i) small effects, (ii) measuring the environment and neural phenotypes, (iii) the absence of detailed mechanisms, and (iv) incorporating development. By actively addressing these challenges, iGxE research is poised to help identify the neural mechanisms underlying genetic and environmental associations with psychopathology.

Document Type: Review
Source: Scopus

Lerman-Sinkoff D.B.a e , Barch D.M.b c d
Network community structure alterations in adult schizophrenia: Identification and localization of alterations
(2016) NeuroImage: Clinical, 10, pp. 96-106. 

DOI: 10.1016/j.nicl.2015.11.011

a Department of Biomedical Engineering, Washington University in St. Louis, Campus Box 1125, 1 Brookings Dr., Saint Louis, MO, United States
b Neuroscience Program, Washington University in St. Louis, 660 S. Euclid Ave., Saint Louis, MO, United States
c Department of Psychological and Brain Sciences, Washington University in St. Louis, 1 Brookings Dr., Saint Louis, MO, United States
d Department of Psychiatry and Radiology, Washington University in St. Louis, 660 S. Euclid Ave., Saint Louis, MO, United States
e Medical Scientist Training Program, Washington University in St. Louis, 660 S. Euclid Ave., Saint Louis, MO, United States

A growing body of literature suggests functional connectivity alterations in schizophrenia. While findings have been mixed, evidence points towards a complex pattern of hyper-connectivity and hypo-connectivity. This altered connectivity can be represented and analyzed using the mathematical frameworks provided by graph and information theory to represent functional connectivity data as graphs comprised of nodes and edges linking the nodes. One analytic technique in this framework is the determination and analysis of network community structure, which is the grouping of nodes into linked communities or modules. This data-driven technique finds a best-fit structure such that nodes in a given community have greater connectivity with nodes in their community than with nodes in other communities. These community structure representations have been found to recapitulate known neural-systems in healthy individuals, have been used to identify novel functional systems, and have identified and localized community structure alterations in a childhood onset schizophrenia cohort. In the present study, we sought to determine whether community structure alterations were present in an adult onset schizophrenia cohort while stringently controlling for sources of imaging artifacts. Group level average graphs in healthy controls and individuals with schizophrenia exhibited visually similar network community structures and high amounts of normalized mutual information (NMI). However, testing of individual subject community structures identified small but significant alterations in community structure with alterations being driven by changes in node community membership in the somatosensory, auditory, default mode, salience, and subcortical networks. © 2015 The Authors.

Author Keywords
Community structure;  Normalized mutual information;  Resting state functional connectivity;  Schizophrenia;  Scrubbing

Document Type: Article
Source: Scopus

Kovacs G.G.a , Ferrer I.b , Grinberg L.T.c d , Alafuzoff I.e , Attems J.f , Budka H.g , Cairns N.J.h , Crary J.F.i ag , Duyckaerts C.j , Ghetti B.k , Halliday G.M.l , Ironside J.W.m , Love S.n , Mackenzie I.R.o , Munoz D.G.p , Murray M.E.q , Nelson P.T.r , Takahashi H.s , Trojanowski J.Q.t , Ansorge O.u , Arzberger T.v , Baborie A.w , Beach T.G.x , Bieniek K.F.q , Bigio E.H.y , Bodi I.z , Dugger B.N.x aa , Feany M.ab , Gelpi , Gentleman , Giaccone , Hatanpaa , Heale R.f , Hof , Hofer M.u , Hortobágyi T.ah , Jellinger , Jicha G.A.aj , Ince P.ak , Kofler , Kövari , Kril , Mann , Matej R.ap , McKee , McLean , Milenkovic I.a as , Montine , Murayama , Lee E.B.t , Rahimi J.a , Rodriguez R.D.av , Rozemüller , Schneider ay , Schultz , Seeley W.c , Seilhean D.j , Smith C.m , Tagliavini , Takao , Thal bc , Toledo J.B.t , Tolnay , Troncoso , Vinters bg , Weis , Wharton S.B.ak , White C.L., IIIaf , Wisniewski bj bk , Woulfe , Yamada , Dickson D.W.q
Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy
(2015) Acta Neuropathologica, pp. 1-16. Article in Press. 

DOI: 10.1007/s00401-015-1509-x

a Institute of Neurology, Medical University of Vienna, AKH 4J, Währinger Gürtel 18-20, Vienna, Austria
b Institute of Neuropathology, Bellvitge University Hospital, University of Barcelona, Hospitalet de Llobregat, Barcelona, Spain
c Department of Neurology, Memory and Aging Center, University of California, San Francisco, United States
d Department of Pathology, LIM-22, University of Sao Paulo Medical School, Sao Paulo, Brazil
e Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
f Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, United Kingdom
g Institute of Neuropathology, University Hospital Zürich, Zurich, Switzerland
h Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
i Department of Pathology, Friedman Brain Institute, and the Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, United States
j Neuropathology Department, Hopital de La Salpetrière, AP-HP, UPMC-Sorbonne-University, Paris, France
k Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
l GMH-Neuroscience Research Australia and the University of New South Wales, Sydney, NSW, Australia
m Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
n Institute of Clinical Neurosciences, University of Bristol, Learning and Research Level 2, Southmead Hospital, Bristol, United Kingdom
o Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
p Division of Pathology, St. Michael’s Hospital, 30 Bond St, Toronto, ON, Canada
q Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, United States
r Department of Pathology and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, United States
s Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan
t Department of Pathology and Laboratory Medicine of the Perelman School of Medicine, Center for Neurodegenerative Disease Research, Institute On Aging, University of Pennsylvania, Philadelphia, United States
u Department of Neuropathology, John Radcliffe Hospital, Oxford, United Kingdom
v Department of Psychiatry and Psychotherapy, Centre for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany
w Department of Neuropathology, Walton Centre, Liverpool, United Kingdom
x Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, United States
y Northwestern ADC Neuropathology Core, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
z Clinical Neuropathology, King’s College Hospital, London Neurodegenerative Brain Bank, London, United Kingdom
aa Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, CA, United States
ab Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
ac Neurological Tissue Bank of the Biobank-Hospital Clinic-IDIBAPS, Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain
ad Department of Medicine, Imperial College London, London, United Kingdom
ae IRCCS Foundation “Carlo Besta” Neurological Institute, Milan, Italy
af Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, United States
ag Fishberg Department of Neuroscience, Friedman Brain Institute, and Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States
ah Department of Neuropathology, Faculty of Medicine, Institute of Pathology, University of Debrecen, Nagyerdei krt. 98, Debrecen, Hungary
ai Institute of Clinical Neurobiology, Alberichgasse 5/13, Vienna, Austria
aj Department of Neurology and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, United States
ak Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, United Kingdom
al Department of Pathology, University of Pittsburgh, Pittsburgh, PA, United States
am Department of Mental Health and Psychiatry, University Hospitals and University of Geneva School of Medicine, Geneva, Switzerland
an Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
ao Institute of Brain, Behaviour and Mental Health, Manchester University Faculty of Medical and Health Sciences, Manchester, United Kingdom
ap Department of Pathology and Molecular Medicine, Thomayer Hospital, Prague 4, Czech Republic
aq Department of Neurology and Pathology, Boston University School of Medicine and VA Healthcare System, Boston, MA, United States
ar Department of Anatomical Pathology, Alfred Hospital, Prahran, VIC, Australia
as Department of Neurology, Medical University of Vienna, Vienna, Austria
at Department of Pathology, University of Washington, Seattle, WA, United States
au Department of Neuropathology (The Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan
av Physiopathology in Aging Lab/Brazilian Aging Brain Study Group-LIM22, University of Sao Paulo Medical School, Sao Paulo, Brazil
aw Netherlands Brainbank and Department of Pathology, VU University Medical Center, Amsterdam, Netherlands
ax Department of Pathology, Rush University Medical Center, Chicago, IL, United States
ay Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, United States
az Institute of Neuroanatomy, Centre for Biomedicine and Medical Technology Mannheim, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
ba Department of Neurology, Saitama Medical University International Medical Center, Saitama, Japan
bb Laboratory of Neuropathology, Institute of Pathology, University of Ulm, Ulm, Germany
bc Department of Neuroscience, KU-Leuven, Louvain, Belgium
bd Institute of Pathology, University Hospital Basel, Basel, Switzerland
be Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
bf Section of Neuropathology, Department of Pathology and Laboratory Medicine, Brain Research Institute, University of California, Los Angeles (UCLA) Medical Center and David Geffen School of Medicine, Los Angeles, CA, United States
bg Department of Neurology, Brain Research Institute, University of California, Los Angeles (UCLA) Medical Center and David Geffen School of Medicine, Los Angeles, CA, United States
bh Department of Pathology and Neuropathology, Laboratory of Neuropathology, Neuromed Campus, Kepler University Hospital, Medical School, Johannes Kepler University, Linz, Austria
bi Department of Neurology, Center for Cognitive Neurology, New York University School of Medicine, ERSP, 450 East 29th Street, New York, NY, United States
bj Department of Pathology, Center for Cognitive Neurology, New York University School of Medicine, ERSP, 450 East 29th Street, New York, NY, United States
bk Department of Psychiatry, Center for Cognitive Neurology, New York University School of Medicine, ERSP, 450 East 29th Street, New York, NY, United States
bl Department of Pathology and Laboratory Medicine, Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada
bm Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan

Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or granular immunopositivity, typically in gray matter. Various forms of ARTAG may coexist in the same brain and might reflect different pathogenic processes. Based on morphology and anatomical distribution, ARTAG can be distinguished from primary tauopathies, but may be concurrent with primary tauopathies or other disorders. We recommend four steps for evaluation of ARTAG: (1) identification of five types based on the location of either morphologies of tau astrogliopathy: subpial, subependymal, perivascular, white matter, gray matter; (2) documentation of the regional involvement: medial temporal lobe, lobar (frontal, parietal, occipital, lateral temporal), subcortical, brainstem; (3) documentation of the severity of tau astrogliopathy; and (4) description of subregional involvement. Some types of ARTAG may underlie neurological symptoms; however, the clinical significance of ARTAG is currently uncertain and awaits further studies. The goal of this proposal is to raise awareness of astroglial tau pathology in the aged brain, facilitating communication among neuropathologists and researchers, and informing interpretation of clinical biomarkers and imaging studies that focus on tau-related indicators. © 2015 Springer-Verlag Berlin Heidelberg

Author Keywords
Aging;  ARTAG;  Tau;  Tau astrogliopathy

Document Type: Article in Press
Source: Scopus

Poldrack R.A.a b c d , Laumann T.O.e , Koyejo O.d , Gregory B.c , Hover A.c , Chen M.-Y.a , Gorgolewski K.J.d , Luci J.b c , Joo S.J.a , Boyd R.L.a , Hunicke-Smith S.f , Simpson Z.B.g , Caven T.h , Sochat V.i , Shine J.M.d , Gordon E.e , Snyder A.Z.e , Adeyemo B.e , Petersen S.E.e , Glahn D.C.j k , Mckay D.R.j k , Curran J.E.l , Göring H.H.H.m , Carless M.A.m , Blangero J.l , Dougherty R.n , Leemans A.o , Handwerker D.A.p , Frick L.c , Marcotte E.M.g q , Mumford J.A.a
Long-term neural and physiological phenotyping of a single human
(2015) Nature Communications, 6, art. no. 8885, . 

DOI: 10.1038/ncomms9885

a Department of Psychology, University of Texas, Austin, TX, United States
b Department of Neuroscience, University of Texas, Austin, TX, United States
c Imaging Research Center, University of Texas, Austin, TX, United States
d Department of Psychology, Stanford University, Stanford, CA, United States
e Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
f Genome Sequencing and Analysis Facility, University of Texas, Austin, TX, United States
g Center for Systems and Synthetic Biology, University of Texas, Austin, TX, United States
h University Medical Center Brackenridge, Austin, TX, United States
i Biomedical Informatics Program, Stanford University, Stanford, CA, United States
j Olin Neuropsychiatry Research Center, Institute of Living, Hartford, CT, United States
k Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States
l South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, United States
m Texas Biomedical Research Institute, San Antonio, TX, United States
n Center for Neurobiological Imaging, Stanford University, Stanford, CA, United States
o Image Sciences Institute, University Medical Center Utrecht, Utrecht, Netherlands
p National Institute of Mental Health (NIMH), Bethesda, MD, United States
q Department of Molecular Biosciences, University of Texas, Austin, TX, United States

Psychiatric disorders are characterized by major fluctuations in psychological function over the course of weeks and months, but the dynamic characteristics of brain function over this timescale in healthy individuals are unknown. Here, as a proof of concept to address this question, we present the MyConnectome project. An intensive phenome-wide assessment of a single human was performed over a period of 18 months, including functional and structural brain connectivity using magnetic resonance imaging, psychological function and physical health, gene expression and metabolomics. A reproducible analysis workflow is provided, along with open access to the data and an online browser for results. We demonstrate dynamic changes in brain connectivity over the timescales of days to months, and relations between brain connectivity, gene expression and metabolites. This resource can serve as a testbed to study the joint dynamics of human brain and metabolic function over time, an approach that is critical for the development of precision medicine strategies for brain disorders.

Document Type: Article
Source: Scopus

Reinfjell T.a , Kårstad S.B.a , Berg-Nielsen T.S.a , Luby J.L.b , Wichstrøm L.a
Predictors of change in depressive symptoms from preschool to first grade
(2015) Development and Psychopathology, pp. 1-14. Article in Press. 

DOI: 10.1017/S0954579415001170

a Norwegian University of Science and Technology
b Washington University School of Medicine

Children's depressive symptoms in the transition from preschool to school are rarely investigated. We therefore tested whether children's temperament (effortful control and negative affect), social skills, child psychopathology, environmental stressors (life events), parental accuracy of predicting their child's emotion understanding (parental accuracy), parental emotional availability, and parental depression predict changes in depressive symptoms from preschool to first grade. Parents of a community sample of 995 4-year-olds were interviewed using the Preschool Age Psychiatric Assessment. The children and parents were reassessed when the children started first grade (n = 795). The results showed that DSM-5 defined depressive symptoms increased. Child temperamental negative affect and parental depression predicted increased, whereas social skills predicted decreased, depressive symptoms. However, such social skills were only protective among children with low and medium effortful control. Further, high parental accuracy proved protective among children with low effortful control and high negative affect. Thus, interventions that treat parental depression may be important for young children. Children with low effortful control and high negative affect may especially benefit from having parents who accurately perceive their emotional understanding. Efforts to enhance social skills may prove particularly important for children with low or medium effortful control. Copyright © Cambridge University Press 2015

Document Type: Article in Press
Source: Scopus

Odia Y.a , Iwamoto F.M.a , Moustakas A.b , Fraum T.J.c , Salgado C.A.d , Li A.e , Kreisl T.N.a , Sul J.f , Butman J.A.g , Fine H.A.h
A phase II trial of enzastaurin (LY317615) in combination with bevacizumab in adults with recurrent malignant gliomas
(2015) Journal of Neuro-Oncology, pp. 1-9. Article in Press. 

DOI: 10.1007/s11060-015-2020-x

a Neuro-Oncology Division, Neurological Institute of New York, Columbia University College of Physicians and Surgeons, 710 West 168th Street, 9th Floor, NI 9-017, New York, NY, United States
b University of Vermont Medical Center, 89 South Williams Street, Burlington, VT, United States
c Mallinckrodt Institute of Radiology, Washington University School of Medicine, Campus Box 8131, 510 S. Kingshighway Blvd., Saint Louis, MO, United States
d University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD, United States
e Center for Cancer Research, National Cancer Institute, Building 37, Room 1142, Bethesda, MD, United States
f Federal Drug Administration, 10903 New Hampshire Ave, Bldg WO22 Rm 2331, Silver Spring, MD, United States
g Department of Radiology, National Institutes of Health Clinical Center, Building 10, Clinical Center 10 Center Drive, MSC 1074, Bethesda, MD, United States
h Division of Neuro-Oncology, Director of the Brain Tumor Center, New York-Presbyterian Hospital/Weill Cornell Medical Center, 1305 York Avenue, 9th Floor, New York, NY, United States

We evaluated the efficacy of combination enzastaurin (LY317615) and bevacizumab for recurrent malignant gliomas and explored serologic correlates. We enrolled 81 patients with glioblastomas (GBM, n = 40) and anaplastic gliomas (AG, n = 41). Patients received enzastaurin as a loading dose of 1125 mg, followed by 500 or 875 mg daily for patients on non-enzyme-inducing or enzyme-inducing antiepileptics, respectively. Patients received bevacizumab 10 mg/kg intravenously biweekly. Clinical evaluations were repeated every 4 weeks. Magnetic resonance imaging was obtained at baseline and every 8 weeks from treatment onset. Phosphorylated glycogen synthase kinase (GSK)-3 levels from peripheral blood mononuclear cells (PBMCs) were checked with each MRI. Median overall survival was 7.5 and 12.4 months for glioblastomas and anaplastic glioma cohorts, with median progression-free survivals of 2.0 and 4.4 months, respectively. Of GBM patients, 3/40 (7.5 %) were not evaluable, while 8/37 (22 %) had partial or complete response and 20/37 (54 %) had stable disease for 2+ months. Of the 39 evaluable AG patients, 18 (46 %) had an objective response, and 16 (41 %) had stable disease for 2+ months. The most common grade 3+ toxicities were lymphopenia (15 %), hypophosphatemia (8.8 %) and thrombotic events (7.5 %). Two (2.5 %) GBM patients died suddenly; another death (1.3 %) occurred from intractable seizures. Phosphorylated GSK-3 levels from PBMCs did not correlate with treatment response. A minimally important improvement in health-related quality of life was self-reported in 7–9/24 (29.2–37.5 %). Early response based on Levin criteria was significantly associated with significantly longer progression free survival for glioblastomas. Enzastaurin (LY317615) in combination with bevacizumab for recurrent malignant gliomas is well-tolerated, with response and progression-free survival similar to bevacizumab monotherapy. © 2015 Springer Science+Business Media New York (outside the USA)

Author Keywords
Bevacizumab;  Enzastaurin;  Glioblastoma;  Glioma;  Trial

Document Type: Article in Press
Source: Scopus

Storm B.C.a , Bui D.C.b
Retrieval-practice task affects relationship between working memory capacity and retrieval-induced forgetting
(2015) Memory, pp. 1-12. Article in Press. 

DOI: 10.1080/09658211.2015.1117640

a Department of Psychology, University of California, Santa Cruz, CA, USA
b Psychological and Brain Sciences, Washington University in Saint Louis, Saint Louis, MO, USA

Retrieving a subset of items from memory can cause forgetting of other items in memory, a phenomenon referred to as retrieval-induced forgetting (RIF). Individuals who exhibit greater amounts of RIF have been shown to also exhibit superior working memory capacity (WMC) and faster stop-signal reaction times (SSRTs), results which have been interpreted as suggesting that RIF reflects an inhibitory process that is mediated by the processes of executive control. Across four experiments, we sought to further elucidate this issue by manipulating the way in which participants retrieved items during retrieval practice and examining how the resulting effects of forgetting correlated with WMC (Experiments 1–3) and SSRT (Experiment 4). Significant correlations were observed when participants retrieved items from an earlier study phase (within-list retrieval practice), but not when participants generated items from semantic memory (extra-list retrieval practice). These results provide important new insight into the role of executive-control processes in RIF. © 2015 Taylor & Francis

Author Keywords
executive control;  inhibition;  Retrieval-induced forgetting;  stop-signal reaction time;  working memory capacity

Document Type: Article in Press
Source: Scopus

Tahsili-Fahadan P.a , Yahyavi-Firouz-Abadi N.b , Keyrouz S.G.a , Pestronk A.c
Bicaudate infarcts in the setting of congenital absence of A1 segment
(2015) Neurology: Clinical Practice, 5 (6), pp. 540-541. 

DOI: 10.1212/CPJ.0000000000000163

a Department of Neurology, Washington University, St. Louis, MO, United States
b Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO, United States
c Departments of Neurology, Pathology, and Immunology, Washington University, St. Louis, MO, United States

A 51-year-old woman with a history of hypertension and smoking presented with sudden onset of confabulation, delusions, and blunted affect. She was oriented to time, place, and person with intact language, strength coordination, and sensation. Gait was slow and wide-based. Serum and CSF yielded no abnormalities. Brain MRI showed bilateral caudate infarcts (figure 1). Cerebral angiography did not provide evidence of dissection or stenosis of the internal carotid artery or major atherosclerosis intracranially or involving the aortic arch. However, it showed an embolus in the right A1, with congenital absence of the left A1 segment; there was a thrombus at the origin of the right internal carotid artery (figure 2). No source of thromboembolism was identified on transthoracic echocardiography. Infarction spared the more distal cortical branches of anterior cerebral artery territories because these benefited from a retrograde filling through middle cerebral artery and posterior cerebral artery pial collaterals, more developed on the left. This congenital vascular variant, one that clinicians should be cognizant of, leads to the bilateral nature of the infarcts.1,2 © American Academy of Neurology.

Document Type: Article
Source: Scopus

Sun S.Q., Cai C., Murphy R.K.J., DeWees T., Dacey R.G., Grubb R.L., Rich K.M., Zipfel G.J., Dowling J.L., Leuthardt E.C., Simpson J.R., Robinson C.G., Chicoine M.R., Perrin R.J., Huang J., Kim A.H.
Radiation Therapy for Residual or Recurrent Atypical Meningioma: The Effects of Modality, Timing, and Tumor Pathology on Long-Term Outcomes
(2015) Neurosurgery, . Article in Press. 

DOI: 10.1227/NEU.0000000000001160

‡Washington University School of Medicine, St. Louis, Missouri; §Department of Pathology and Immunology, Washington University, St. Louis, Missouri; ¶Department of Neurosurgery, Washington University, St. Louis, Missouri; ?Department of Radiation Oncology, Washington University, St. Louis, Missouri

BACKGROUND:: Optimal use of stereotactic radiosurgery (SRS) vs external beam radiation therapy (EBRT) for treatment of residual/recurrent atypical meningioma is unclear. OBJECTIVE:: To analyze features associated with progression after radiation therapy. METHODS:: Fifty radiation-naive patients who received SRS or EBRT for residual and/or recurrent atypical meningioma were examined for predictors of progression using Cox regression and Kaplan-Meier analyses. RESULTS:: Thirty-two patients (64%) received adjuvant radiation after subtotal resection, 12 patients (24%) received salvage radiation after progression following subtotal resection, and 6 patients (12%) received salvage radiation after recurrence following gross total resection. Twenty-one patients (42%) received SRS (median 18 Gy), and 7 (33%) had tumor progression. Twenty-nine patients (58%) received EBRT (median 54 Gy), and 13 (45%) had tumor progression. Whereas tumor volume (P = .5), SRS vs EBRT (P = .5), and adjuvant vs salvage (P = .3) were not associated with progression after radiation therapy, spontaneous necrosis (HR = 82.3, P = .0002), embolization necrosis (HR = 15.6, P = .03), and brain invasion (HR = 3.8, P = .008) predicted progression in univariate and multivariate analyses. Tumors treated with SRS/EBRT had 2- and 5-year actuarial locoregional control rates of 91%/88% and 71%/69%, respectively. Tumors with spontaneous necrosis, embolization necrosis, and no necrosis had 2- and 5-year locoregional control rates of 76%, 92%, and 100% and 36%, 73%, and 100%, respectively (P < .001). CONCLUSION:: This study suggests that necrosis may be a negative predictor of radiation response regardless of radiation timing or modality. ABBREVIATIONS:: AM, atypical meningiomaEBRT, external beam radiation therapyGTR, gross total resectionLC, locoregional controlOS, overall survivalPOE, preoperative embolizationRT, radiation therapySRS, stereotactic radiosurgerySTR, subtotal resection Copyright © by the Congress of Neurological Surgeons

Document Type: Article in Press
Source: Scopus

Schill E.M.a , Lake J.I.a , Tusheva O.A.a , Nagy N.b c , Bery S.K.d , Foster L.e , Avetisyan M.a , Johnson S.L.f , Stenson W.F.e , Goldstein A.M.b , Heuckeroth R.O.d
Ibuprofen slows migration and inhibits bowel colonization by enteric nervous system precursors in zebrafish, chick and mouse
(2015) Developmental Biology, . Article in Press. 

DOI: 10.1016/j.ydbio.2015.09.023

a Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA
b Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St., Boston, MA 02114, USA
c Department of Human Morphology and Developmental Biology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
d Department of Pediatrics, The Children's Hospital of Philadelphia Research Institute and the Perelman School of Medicine at the University of Pennsylvania, Abramson Research Center, 3615 Civic Center Blvd, Philadelphia, PA 19104, USA
e Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA
f Department of Genetics, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA

Hirschsprung Disease (HSCR) is a potentially deadly birth defect characterized by the absence of the enteric nervous system (ENS) in distal bowel. Although HSCR has clear genetic causes, no HSCR-associated mutation is 100% penetrant, suggesting gene-gene and gene-environment interactions determine HSCR occurrence. To test the hypothesis that certain medicines might alter HSCR risk we treated zebrafish with medications commonly used during early human pregnancy and discovered that ibuprofen caused HSCR-like absence of enteric neurons in distal bowel. Using fetal CF-1 mouse gut slice cultures, we found that ibuprofen treated enteric neural crest-derived cells (ENCDC) had reduced migration, fewer lamellipodia and lower levels of active RAC1/CDC42. Additionally, inhibiting ROCK, a RHOA effector and known RAC1 antagonist, reversed ibuprofen effects on migrating mouse ENCDC in culture. Ibuprofen also inhibited colonization of Ret+/- mouse bowel by ENCDC in vivo and dramatically reduced bowel colonization by chick ENCDC in culture. Interestingly, ibuprofen did not affect ENCDC migration until after at least three hours of exposure. Furthermore, mice deficient in Ptgs1 (COX 1) and Ptgs2 (COX 2) had normal bowel colonization by ENCDC and normal ENCDC migration in vitro suggesting COX-independent effects. Consistent with selective and strain specific effects on ENCDC, ibuprofen did not affect migration of gut mesenchymal cells, NIH3T3, or WT C57BL/6 ENCDC, and did not affect dorsal root ganglion cell precursor migration in zebrafish. Thus, ibuprofen inhibits ENCDC migration in vitro and bowel colonization by ENCDC in vivo in zebrafish, mouse and chick, but there are cell type and strain specific responses. These data raise concern that ibuprofen may increase Hirschsprung disease risk in some genetically susceptible children. © 2015 Elsevier Inc.

Author Keywords
Enteric nervous system development;  Gene-environment interactions;  Migration

Document Type: Article in Press
Source: Scopus

Edwin N.C.a , Khoury M.N.b , Sohal D.c , McCrae K.R.c , Ahluwalia M.S.b , Khorana A.A.c
Recurrent venous thromboembolism in glioblastoma
(2015) Thrombosis Research, . Article in Press. 

DOI: 10.1016/j.thromres.2015.11.027

a Division of Hematology and Medical Oncology, Washington University in St Louis School of Medicine, 660 S Euclid Avenue, Campus Box 8056, St Louis, MO 63110, USA
b Burkhardt Brain Tumor and Neuro Oncology Center, Neurological Institute Cleveland Clinic, 9500 Euclid Avenue, S73 Cleveland, OH 44195, USA
c Department of Hematology and Medical Oncology, Taussig Cancer Institute Cleveland Clinic, 9500 Euclid Avenue, R35 Cleveland, OH 44195, USA

Background: Patients with glioblastoma (GBM) are at increased risk of initial and recurrent venous thromboembolism (VTE) but rates of recurrence and real-world treatment choices are incompletely understood. Objectives: We aim to describe the treatment of incident VTE, report incidence and risk factors for recurrence. Patients/methods: We conducted a retrospective cohort study of consecutive Cleveland Clinic patients with GBM presenting with objectively diagnosed deep vein thrombosis (DVT) or pulmonary embolism (PE) from 2007 to 2013 with at least 6-month follow-up. We collected information on patient demographics, VTE incidence, treatment and recurrence. Data were analyzed using multivariate logistic regression analysis. Results: Of 450 patients with GBM, 145 (32.2%) developed VTE and comprised the study population. Of these, 11 (7.6%) experienced PE, 117 (80.7%) had DVT and 16 (11%) had DVT as well as PE. Fifty five (37.9%) VTE events occurred in the first 30 post-operative days and 56 (38.6%) during chemotherapy. Thirty one (21.4%) patients were untreated. Treatments included enoxaparin (N = 36, 24.8%), warfarin (15, 10.3%) or vena cava filters either alone (N = 39, 26.9%) or in combination with anticoagulation (N = 21, 14.5%). Recurrent VTE occurred in 39 patients (26.9%).In multivariate analysis, lack of long term anticoagulation (HR 11.2, CI 1.5-86.3, p. <. 0.05) and the presence of second primary malignancy (HR 3.69, CI 1.2-11.1, p. <. 0.05) were significantly associated with recurrent VTE. Conclusion: VTE and recurrent VTE are highly prevalent throughout the disease course among patients with GBM. Long term anticoagulation is associated with reduced risk of recurrent VTE but is often not utilized. © 2015 Elsevier Ltd.

Author Keywords
Cancer associated thrombosis;  Deep vein thrombosis;  Glioblastoma multiforme;  Pulmonary embolism;  Venous thromboembolism

Document Type: Article in Press
Source: Scopus

Mcelroy S.L.a b , Mitchell J.E.c , Wilfley D.d , Gasior M.e , Ferreira-Cornwell M.C.e , Mckay M.e , Wang J.f , Whitaker T.e , Hudson J.I.g
Lisdexamfetamine Dimesylate Effects on Binge Eating Behaviour and Obsessive-Compulsive and Impulsive Features in Adults with Binge Eating Disorder
(2015) European Eating Disorders Review, . Article in Press. 

DOI: 10.1002/erv.2418

a University of Cincinnati College of Medicine Cincinnati OH USA
b Lindner Center of HOPE Mason OH USA
c Neuropsychiatric Research Institute Fargo ND USA
d Washington University School of Medicine St. Louis MO USA
e Shire Wayne PA USA
f CSL Behring King of Prussia PA USA (previously employed at Shire)
g McLean Hospital/Harvard Medical School Belmont MA USA

In a published 11-week, placebo-controlled trial, 50 and 70mg/d lisdexamfetamine dimesylate (LDX), but not 30mg/d LDX, significantly reduced binge eating days (primary endpoint) in adults with binge eating disorder (BED). This report provides descriptions of LDX effects on secondary endpoints (Binge Eating Scale [BES]; Three-Factor Eating Questionnaire [TFEQ]; Yale-Brown Obsessive Compulsive Scale modified for Binge Eating [Y-BOCS-BE]; and the Barratt Impulsiveness Scale, version 11 [BIS-11]) from that study. Week 11 least squares mean treatment differences favoured all LDX doses over placebo on the BES (p≤0.03), TFEQ Disinhibition and Hunger subscales (all p<0.05), and Y-BOCS-BE total, obsessive, and compulsive scales (all p≤0.02) and on BIS-11 total score at 70mg/d LDX (p=0.015) and the TFEQ Cognitive Restraint subscale at 30 and 70mg/d LDX (both p<0.05). These findings indicate that LDX decreased global binge eating severity and obsessive-compulsive and impulsive features of BED in addition to binge eating days. Copyright © 2015 John Wiley & Sons, Ltd and Eating Disorders Association

Author Keywords
Binge eating disorder;  Impulsivity;  Lisdexamfetamine dimesylate;  Obsessive-compulsive


Document Type: Article in Press
Source: Scopus

December 16, 2015

Xue Y.a b d , Shen S.Q.a c d , Corbo J.C.a c , Kefalov V.J.a b
Circadian and light-driven regulation of rod dark adaptation
(2015) Scientific Reports, 5, art. no. 17616, . 

DOI: 10.1038/srep17616

a Washington University School of Medicine, St. Louis, MO, United States
b Department of Ophthalmology and Visual Sciences, 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 Graduate Program in Division of Biological and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, United States

Continuous visual perception and the dark adaptation of vertebrate photoreceptors after bright light exposure require recycling of their visual chromophore through a series of reactions in the retinal pigmented epithelium (RPE visual cycle). Light-driven chromophore consumption by photoreceptors is greater in daytime vs. nighttime, suggesting that correspondingly higher activity of the visual cycle may be required. However, as rod photoreceptors are saturated in bright light, the continuous turnover of their chromophore by the visual cycle throughout the day would not contribute to vision. Whether the recycling of chromophore that drives rod dark adaptation is regulated by the circadian clock and light exposure is unknown. Here, we demonstrate that mouse rod dark adaptation is slower during the day or after light pre-exposure. This surprising daytime suppression of the RPE visual cycle was accompanied by light-driven reduction in expression of Rpe65, a key enzyme of the RPE visual cycle. Notably, only rods in melatonin-proficient mice were affected by this daily visual cycle modulation. Our results demonstrate that the circadian clock and light exposure regulate the recycling of chromophore in the RPE visual cycle. This daily melatonin-driven modulation of rod dark adaptation could potentially protect the retina from light-induced damage during the day.

Document Type: Article
Source: Scopus

Hall C.A.a , Simon K.M.b , Lenze E.J.c , Dew M.A.a , Begley A.a c , Butters M.A.a , Blumberger D.M.d , Stack J.A.a c , Mulsant B.d e , Reynolds C.F.a

Depression remission rates among older black and white adults: Analyses from the IRL-GREY trial
(2015) Psychiatric Services, 66 (12), pp. 1303-1311. 

DOI: 10.1176/

a Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
b Department of Psychiatry, Morehouse University School of Medicine, Atlanta, United States
c NIMH Center for Late Life Depression Prevention and Treatment, University of Pittsburgh, United States
d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
e Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

Objective: This study explored whether older black and white adults with major depressive disorder differed in rates of remission or attrition during open-label treatment with venlafaxine and supportive care. Methods: A total of 47 black (10%) and 412 white (90%) adults age 60 were treated with open-label venlafaxine extended-release (#300 mg per day) for 12-14 weeks during the initial phase of an multisite, randomized, placebocontrolled augmentation trial. Participants were help-seeking older adults with nonpsychotic major depressive disorder (single or recurrent episode) referred from specialty clinics, primary care practices, advertisements, and research programs. Remission was defined as a Montgomery-Asberg Depression Rating Scale score of #10 for two consecutive assessments at the end of 12 weeks. Kaplan-Meier curves displayed time to dropout and time to initial remission. Cox proportional hazards models assessed differences in attrition and remission rates. Results: Black participants had greater baseline general medical comorbidity, worse physical health-related quality of life, and poorer cognitive function than white participants. White participants were more likely to have received an adequate trial of antidepressant and psychotherapy before study entry. Baseline depression severity, depression duration, age at onset, and recurrence history did not differ between groups. The groups had similar final doses of venlafaxine and similar rates of attrition and remission. Side-effect profiles were comparable between the groups. Conclusions: Despite greater medical comorbidity, lower cognitive function, and less adequate prior exposure to antidepressant treatment and psychotherapy, black participants were no more likely to discontinue antidepressant pharmacotherapy and experienced a rate of remission comparable to white participants.

Document Type: Article
Source: Scopus

Chen L.-S.a , Baker T.B.b , Bierut L.J.a
The value of control conditions for evaluating pharmacogenetic effects
(2015) Pharmacogenomics, 16 (18), pp. 2005-2006. 

DOI: 10.2217/pgs.15.143

a Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, United States
b Tobacco Research and Intervention, University of Wisconsin, School of Medicine, Madison, WI, United States

Document Type: Letter
Source: Scopus


Peng C.-Z.a b , Grant J.D.a , Heath A.C.a , Reiersen A.M.a , Mulligan R.C.a , Anokhin A.P.a

Familial influences on the full range of variability in attention and activity levels during adolescence: A longitudinal twin study
(2015) Development and Psychopathology, pp. 1-10. Article in Press. 

DOI: 10.1017/S0954579415001091

a Washington University School of Medicine
b University of Missouri

To investigate familial influences on the full range of variability in attention and activity across adolescence, we collected maternal ratings of 339 twin pairs at ages 12, 14, and 16, and estimated the transmitted and new familial influences on attention and activity as measured by the Strengths and Weaknesses of Attention-Deficit/Hyperactivity Disorder Symptoms and Normal Behavior Scale. Familial influences were substantial for both traits across adolescence: genetic influences accounted for 54%–73% (attention) and 31%–73% (activity) of the total variance, and shared environmental influences accounted for 0%–22% of the attention variance and 13%–57% of the activity variance. The longitudinal stability of individual differences in attention and activity was largely accounted for by familial influences transmitted from previous ages. Innovations over adolescence were also partially attributable to familial influences. Studying the full range of variability in attention and activity may facilitate our understanding of attention-deficit/hyperactivity disorder's etiology and intervention. Copyright © Cambridge University Press 2015

Document Type: Article in Press
Source: Scopus

Hawrylycz M.a , Miller J.A.a , Menon V.a , Feng D.a , Dolbeare T.a , Guillozet-Bongaarts A.L.a , Jegga A.G.b , Aronow B.J.b , Lee C.-K.a , Bernard A.a , Glasser M.F.c , Dierker D.L.c , Menche J.d e f , Szafer A.a , Collman F.a , Grange P.g , Berman K.A.h , Mihalas S.a , Yao Z.a , Stewart L.i , Barabási A.-L.d e f j k , Schulkin J.l , Phillips J.a , Ng L.a , Dang C.a , R Haynor D.m , Jones A.a , Van Essen D.C.c , Koch C.a , Lein E.a
Canonical genetic signatures of the adult human brain
(2015) Nature Neuroscience, 18 (12), pp. 1832-1844. Cited 1 time.

DOI: 10.1038/nn.4171

a Allen Institute for Brain Science, Seattle, WA, United States
b Division of Biomedical Informatics, Cincinnati Children's Hospital and Medical Center, Cincinnati, OH, United States
c Department of Anatomy and Neurobiology, Washington University, St. Louis, MO, United States
d Center for Complex Networks Research, Northeastern University, Boston, MA, United States
e Department of Physics, Northeastern University, Boston, MA, United States
f Center for Network Science, Central European University, Budapest, Hungary
g Department of Mathematical Sciences, Xi'an Jiaotong-Liverpool University, Jiangsu, China
h Department of Electrical Engineering and Computing Systems, University of Cincinnati, Cincinnati, OH, United States
i Institute for Protein Design, University of Washington, Seattle, WA, United States
j Center for Cancer Systems Biology, Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, United States
k Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
l Department of Neuroscience, Georgetown University, Washington, DC, United States
m Department of Radiology, University of Washington, Seattle, WA, United States

The structure and function of the human brain are highly stereotyped, implying a conserved molecular program responsible for its development, cellular structure and function. We applied a correlation-based metric called differential stability to assess reproducibility of gene expression patterning across 132 structures in six individual brains, revealing mesoscale genetic organization. The genes with the highest differential stability are highly biologically relevant, with enrichment for brain-related annotations, disease associations, drug targets and literature citations. Using genes with high differential stability, we identified 32 anatomically diverse and reproducible gene expression signatures, which represent distinct cell types, intracellular components and/or associations with neurodevelopmental and neurodegenerative disorders. Genes in neuron-associated compared to non-neuronal networks showed higher preservation between human and mouse; however, many diversely patterned genes displayed marked shifts in regulation between species. Finally, highly consistent transcriptional architecture in neocortex is correlated with resting state functional connectivity, suggesting a link between conserved gene expression and functionally relevant circuitry. © 2015 Nature America, Inc.

Document Type: Article
Source: Scopus

Shaw T.N.a , Stewart-Hutchinson P.J.b c , Strangward P.a , Dandamudi D.B.d , Coles J.A.e , Villegas-Mendez A.a , Gallego-Delgado J.f , van Rooijen N.g , Zindy E.h , Rodriguez A.f , Brewer J.M.e , Couper K.N.a , Dustin M.L.b i
Perivascular Arrest of CD8+ T Cells Is a Signature of Experimental Cerebral Malaria
(2015) PLoS Pathogens, 11 (11), art. no. e1005210, 33 p. 

DOI: 10.1371/journal.ppat.1005210

a University of Manchester, Manchester, United Kingdom
b Molecular Pathogenesis Program, Helen L. and Martin S. Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, New York, NY, United States
c Department of Pediatric Research, Washington University School of Medicine, St. Louis, MO, United States
d Immunology and Inflammation Program, Helen L. and Martin S. Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, New York, NY, United States
e Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
f Department of Microbiology, New York University School of Medicine, New York, NY, United States
g Department of Molecular Cell Biology, VU Medical Center, Amsterdam, Netherlands
h The Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, United Kingdom
i The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics and Musculoskeletal Sciences, The University of Oxford, Headington, United Kingdom

There is significant evidence that brain-infiltrating CD8+ T cells play a central role in the development of experimental cerebral malaria (ECM) during Plasmodium berghei ANKA infection of C57BL/6 mice. However, the mechanisms through which they mediate their pathogenic activity during malaria infection remain poorly understood. Utilizing intravital two-photon microscopy combined with detailed ex vivo flow cytometric analysis, we show that brain-infiltrating T cells accumulate within the perivascular spaces of brains of mice infected with both ECM-inducing (P. berghei ANKA) and non-inducing (P. berghei NK65) infections. However, perivascular T cells displayed an arrested behavior specifically during P. berghei ANKA infection, despite the brain-accumulating CD8+ T cells exhibiting comparable activation phenotypes during both infections. We observed T cells forming long-term cognate interactions with CX3CR1-bearing antigen presenting cells within the brains during P. berghei ANKA infection, but abrogation of this interaction by targeted depletion of the APC cells failed to prevent ECM development. Pathogenic CD8+ T cells were found to colocalize with rare apoptotic cells expressing CD31, a marker of endothelial cells, within the brain during ECM. However, cellular apoptosis was a rare event and did not result in loss of cerebral vasculature or correspond with the extensive disruption to its integrity observed during ECM. In summary, our data show that the arrest of T cells in the perivascular compartments of the brain is a unique signature of ECM-inducing malaria infection and implies an important role for this event in the development of the ECM-syndrome. © 2015 Shaw et al.

Document Type: Article
Source: Scopus

Guerreiro R.a , Escott-Price V.b , Darwent L.a , Parkkinen L.c , Ansorge O.c , Hernandez D.G.d e , Nalls M.A.d , Clark L.f g , Honig L.f g , Marder K.f h , van der Flier W.i , Holstege H.i , Louwersheimer E.i , Lemstra A.i , Scheltens P.i , Rogaeva E.j , St George-Hyslop P.j k , Londos E.l , Zetterberg H.a m , Ortega-Cubero S.n o , Pastor P.n o p , Ferman T.J.q , Graff-Radford N.R.r , Ross O.A.s , Barber I.t , Braae A.t , Brown K.t , Morgan K.t , Maetzler W.u , Berg D.u , Troakes C.v , Al-Sarraj S.v , Lashley T.w , Compta Y.w x , Revesz T.w , Lees A.w , Cairns N.J.y , Halliday G.M.z aa , Mann D.ab , Pickering-Brown S.ab , Powell , Lunnon , Lupton , Dickson D.s , Hardy , Singleton A.d , Bras J.a
Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Parkinson's and Alzheimer's diseases
(2015) Neurobiology of Aging, . Article in Press. 

DOI: 10.1016/j.neurobiolaging.2015.10.028

a Department of Molecular Neuroscience, Institute of Neurology, UCL, London, UK
b MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK
c Nuffield Department of Clinical Neurosciences, Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK
d Laboratory of Neurogenetics, National Institutes on Aging, NIH, Bethesda, MD, USA
e German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
f Taub Institute for Alzheimer Disease and the Aging Brain, Columbia University, New York, NY, USA
g Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
h Department of Neurology, Columbia University, New York, NY, USA
i Department Of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands
j Department of Medicine, Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada
k Cambridge Institute for Medical Research, and Cambridge National Institute of Health Research Biomedical Research Unit in Dementia, University of Cambridge, Cambridge, UK
l Clinical Memory Research Unit, Institute of Clinical Sciences Malmö, Lund University, Lund, Sweden
m Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
n Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, (CIMA), University of Navarra, Pamplona, Spain
o CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain
p Memory and Movement Disorders Units, Department of Neurology, University Hospital Mutua de Terrassa, University of Barcelona School of Medicine, Terrassa, Barcelona, Spain
q Departments of Psychiatry and Psychology, Mayo Clinic, Jacksonville, FL, USA
r Department of Neurology, Mayo Clinic, Jacksonville, FL, USA
s Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
t Translation Cell Sciences-Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK
u Hertie Institute for Clinical Brain Research, Department of Neurodegeneration, Center of Neurology, University of Tuebingen, and DZNE, German Center for Neurodegenerative Diseases, Tuebingen, Germany
v MRC London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Department of Clinical Neuroscience, King's College London, London, UK
w Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
x Parkinson's Disease and Movement Disorders Unit, Neurology Service, Clinical Neuroscience Institute (ICN), Hospital Clínic/University of Barcelona/IDIBAPS, Barcelona, Spain
y Department of Neurology, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, Saint Louis, MO, USA
z Neuroscience Research Australia, Sydney, Australia
aa School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia
ab Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK
ac Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
ad Institute of Clinical and Biomedical Science, University of Exeter Medical School, University of Exeter, Exeter, UK
ae Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK

The similarities between dementia with Lewy bodies (DLB) and both Parkinson's disease (PD) and Alzheimer's disease (AD) are many and range from clinical presentation, to neuropathological characteristics, to more recently identified, genetic determinants of risk. Because of these overlapping features, diagnosing DLB is challenging and has clinical implications since some therapeutic agents that are applicable in other diseases have adverse effects in DLB. Having shown that DLB shares some genetic risk with PD and AD, we have now quantified the amount of sharing through the application of genetic correlation estimates, and show that, from a purely genetic perspective, and excluding the strong association at the APOE locus, DLB is equally correlated to AD and PD. © 2015 The Authors.

Author Keywords
Alzheimer's disease;  Dementia with Lewy bodies;  Genetic correlation;  Parkinson's disease

Document Type: Article in Press
Source: Scopus

Nemanich S.T.a , Earhart G.M.a b c
How do age and nature of the motor task influence visuomotor adaptation?
(2015) Gait and Posture, 42 (4), pp. 564-568. 

DOI: 10.1016/j.gaitpost.2015.09.001

a Washington University in St. Louis School of Medicine, St. Louis, MO, United States
b Department of Anatomy and Neurobiology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
c Department of Neurology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States

Visuomotor adaptation with prism glasses is a paradigm often used to understand how the motor system responds to visual perturbations. Both reaching and walking adaptation have been documented, but not directly compared. Because the sensorimotor environment and demands are different between reaching and walking, we hypothesized that characteristics of prism adaptation, namely rates and aftereffects, would be different during walking compared to reaching. Furthermore, we aimed to determine the impact of age on motor adaptation. We studied healthy younger and older adults who performed visually guided reaching and walking tasks with and without prism glasses. We noted age effects on visuomotor adaptation, such that older adults adapted and re-adapted slower compared to younger adults, in accord with previous studies of adaptation in older adults. Interestingly, we also noted that both groups adapted slower and showed smaller aftereffects during walking prism adaptation compared to reaching. We propose that walking adaptation is slower because of the complex multi-effector and multi-sensory demands associated with walking. Altogether, these data suggest that humans can adapt various movement types but the rate and extent of adaptation is not the same across movement types nor across ages. © 2015 Elsevier B.V.

Author Keywords
Aftereffects;  Aging;  Gait adaptation;  Prisms;  Visuomotor adaptation

Document Type: Article
Source: Scopus

Hastings M.K.a , Mueller M.J.a , Woodburn J.b , Strube M.J.c , Commean P.d , Johnson J.E.e , Cheuy V.a , Sinacore D.R.a
Acquired midfoot deformity and function in individuals with diabetes and peripheral neuropathy
(2015) Clinical Biomechanics, . Article in Press. 

DOI: 10.1016/j.clinbiomech.2015.11.001

a Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO 63110, USA
b Institute for Applied Health Research, Glasgow Caledonian University, Glasgow City, UK
c Department of Psychology, Washington University in St. Louis, MO 63105, USA
d Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA
e Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA

Background: Diabetes mellitus related medial column foot deformity is a major contributor to ulceration and amputation. However, little is known about the relationship between medial column alignment and function and the integrity of the soft tissues that support and move the medial column. The purposes of this study were to determine the predictors of medial column alignment and function in people with diabetes and peripheral neuropathy. Methods: 23 participants with diabetes and neuropathy had radiographs, heel rise kinematics, magnetic resonance imaging and isokinetic muscle testing to measure: 1) medial column alignment (Meary's angle - the angle between the 1st metatarsal longitudinal axis and the talar head and neck), 2) medial column function (forefoot relative to hindfoot plantarflexion during heel rise), 3) intrinsic foot muscle and fat volume, ratio of posterior tibialis to flexor digitorum tendon volume, 4) plantar fascia function (Meary's angle change from toes flat to extended) and 5) plantarflexor peak torque. Predictors of medial column alignment and function were determined using simultaneous entry multiple regression. Findings: Posterior tibialis to flexor digitorum tendon volume ratio and intrinsic foot muscle volume were significant predictors of medial column alignment (P <. .05), accounting for 44% of the variance. Intrinsic foot fat volume and plantarflexor peak torque were significant predictors of medial column function (P <. .05), accounting for 37% of the variance. Interpretation: Deterioration of medial column supporting structures predicted alignment and function. Prospective research is required to monitor alignment, structure, and function over time to inform early intervention strategies to prevent deformity, ulceration, and amputation. © 2015 Elsevier Ltd.

Author Keywords
Intrinsic foot muscle;  Muscle volume;  Plantarflexor power;  Posterior tibialis tendon

Document Type: Article in Press
Source: Scopus

Huang J.a , Liu Y.a , Filas B.a , Gunhaga L.c , Beebe D.C.a b
Negative and positive auto-regulation of BMP expression in early eye development
(2015) Developmental Biology, . Article in Press. 

DOI: 10.1016/j.ydbio.2015.09.009

a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA
b Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA
c Umeå Centre for Molecular Medicine, Umeå University, Umeå, Sweden

Previous results have shown that Bone Morphogenetic Protein (BMP) signaling is essential for lens specification and differentiation. How BMP signals are regulated in the prospective lens ectoderm is not well defined. To address this issue we have modulated BMP activity in a chicken embryo pre-lens ectoderm explant assay, and also studied transgenic mice, in which the type I BMP receptors, Bmpr1a and Acvr1, are deleted from the prospective lens ectoderm. Our results show that chicken embryo pre-lens ectoderm cells express BMPs and require BMP signaling for lens specification in vitro, and that in vivo inhibition of BMP signals in the mouse prospective lens ectoderm interrupts lens placode formation and prevents lens invagination. Furthermore, our results provide evidence that BMP expression is negatively auto-regulated in the lens-forming ectoderm, decreasing when the tissue is exposed to exogenous BMPs and increasing when BMP signaling is prevented. In addition, eyes lacking BMP receptors in the prospective lens placode develop coloboma in the adjacent wild type optic cup. In these eyes, Bmp7 expression increases in the ventral optic cup and the normal dorsal-ventral gradient of BMP signaling in the optic cup is disrupted. Pax2 becomes undetectable and expression of Sfrp2 increases in the ventral optic cup, suggesting that increased BMP signaling alter their expression, resulting in failure to close the optic fissure. In summary, our results suggest that negative and positive auto-regulation of BMP expression is important to regulate early eye development. © 2015.

Author Keywords
Auto-regulation;  BMP;  Coloboma;  Development;  Lens;  Specification

Document Type: Article in Press
Source: Scopus

Pomara N.a b , Lee S.H.a , Bruno D.a b c , Silber T.a d , Greenblatt D.J.e , Petkova E.a b , Sidtis J.J.a b
Adverse performance effects of acute lorazepam administration in elderly long-term users: Pharmacokinetic and clinical predictors
(2015) Progress in Neuro-Psychopharmacology and Biological Psychiatry, 56, pp. 129-135. 

DOI: 10.1016/j.pnpbp.2014.08.014

a Nathan Kline Institute, Orangeburg, NY, United States
b New York University School of Medicine, New York, NY, United States
c Liverpool Hope University, Liverpool, United Kingdom
d Washington University in St. Louis, St. Louis, MO, United States
e Tufts University School of Medicine, Boston, MA, United States

Background: The benzodiazepine lorazepam is widely utilized in the treatment of elderly individuals with anxiety disorders and related conditions. Negative effects of acute lorazepam administration on cognitive performance, especially memory, have been reported in both previously untreated elderly and in individuals who have received short term (up to three weeks) treatment with therapeutic doses. However, it remains unclear if these adverse cognitive effects also persist after long-term use, which is frequently found in clinical practice. Methods: Cognitively intact elderly individuals (n= 37) on long-term (at least three months) daily treatment with lorazepam were studied using a double-blind placebo-controlled cross-over study design. Subjects were administered their highest daily unit dose of lorazepam (0.25-3.00. mg) or placebo on different days, approximately 1. week apart in a random order, and were assessed on memory, psychomotor speed, and subjective mood states. Results: Subjects had significantly poorer recall and slowed psychomotor performance following acute lorazepam administration. There were no significant effects on self-ratings of mood, sedation, or anxiety in the whole group, but secondary analyses suggested a differential response in subjects with Generalized Anxiety Disorder. Conclusions: The reduced recall and psychomotor slowing that we observed, along with an absence of significant therapeutic benefits, following acute lorazepam administration in elderly long-term users reinforces the importance of cognitive toxicity as a clinical factor in benzodiazepine use, especially in this population. © 2014 Elsevier Inc.

Author Keywords
Aging;  Benzodiazepines;  Cognitive toxicity;  Lorazepam;  Memory loss;  Psychomotor slowing


Document Type: Article
Source: Scopus


December 9, 2015

Brier, M.R.a , Wu, Q.a b , Tanenbaum, A.B.a , Westerhaus, E.T.a , Kharasch, E.D.d , Ances, B.M.a b c
Effect of HAART on Brain Organization and Function in HIV-Negative Subjects
(2015) Journal of Neuroimmune Pharmacology, 10 (4), pp. 517-521. 

DOI: 10.1007/s11481-015-9634-9

a Department of Neurology, School of Medicine, Washington University in St Louis, St Louis, MO, United States
b Department of Biomedical Engineering, Washington University in St Louis, St Louis, MO, United States
c Department of Radiology, Washington University in St Louis, St Louis, MO, United States
d Department of Anesthesiology, Washington University in St Louis, St Louis, MO, United States

HIV causes neural dysfunction in infected individuals. This dysfunction often manifests as cognitive symptoms and can be detected using neuroimaging. Highly active anti-retroviral therapy (HAART), in addition to providing virologic control, has reduced the number of profoundly impaired individuals but more mild forms of neurocognitive disorders remains prevalent. A potential confound in previous studies of HIV-associated cognitive dysfunction is that HAART may be neurotoxic. Thus, observed effects, attributed to HIV, may be in part due to HAART. It is unclear whether and to what extent current medications contribute to observed brain dysfunction. We studied changes in functional connectivity and cerebral blood flow in HIV uninfected (HIV–) individuals before and after being given two common antiretroviral medications: efavirenz and ritonavir. Neither drug was associated with significant changes in functional connectivity or cerebral blood flow. Our results suggests that previous changes in functional connectivity and cerebral blood flow in HIV infected individuals receiving HAART may largely due to the virus and remaining reservoirs and less due to toxic action of these anti-retroviral medications. © 2015, Springer Science+Business Media New York.

Author Keywords
cART;  HAART;  HIV;  Neurotoxicity

Document Type: Article
Source: Scopus

Behrman-Lay, A.M.a , Usher, C.a , Conturo, T.E.b , Correia, S.c , Laidlaw, D.H.d , Lane, E.M.e , Bolzenius, J.a , Heaps, J.M.a , Salminen, L.E.a , Baker, L.M.a , Cabeen, R.d , Akbudak, E.b , Luo, X.f , Yan, P.g , Paul, R.H.a
Fiber bundle length and cognition: a length-based tractography MRI study
(2015) Brain Imaging and Behavior, 9 (4), pp. 765-775. 

DOI: 10.1007/s11682-014-9334-8

a Department of Psychology, University of Missouri – Saint Louis, 1 University Boulevard, Stadler Hall 442C, Saint Louis, MO, United States
b Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway, St. Louis, MO, United States
c Department of Psychiatry & Human Behavior, Alpert Medical School, Brown University, Box G-A, Providence, RI, United States
d Computer Science Department, Brown University, Box 1910, Providence, RI, United States
e Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN, United States
f Department of Biostatistics and Center for Statistical Sciences, Brown University, Box G-S121-7, 121 S, Main Street, Providence, RI, United States
g Center for Computation and Visualization, Brown University, Box 1824, Providence, RI, United States

Executive function (EF) and cognitive processing speed (CPS) are two cognitive performance domains that decline with advanced age. Reduced EF and CPS are known to correlate with age-related frontal-lobe volume loss. However, it remains unclear whether white matter microstructure in these regions is associated with age-related decline in EF and/or CPS. We utilized quantitative tractography metrics derived from diffusion-tensor MRI to investigate the relationship between the mean fiber bundle lengths (FBLs) projecting to different lobes, and EF/CPS performance in 73 healthy aging adults. We measured aspects of EF and CPS with the Trail Making Test (TMT), Color-Word Interference Test, Letter-Number Sequencing (L-N Seq), and Symbol Coding. Results revealed that parietal and occipital FBLs explained a significant portion of variance in EF. Frontal, temporal, and occipital FBLs explained a significant portion of variance in CPS. Shorter occipital FBLs were associated with poorer performance on the EF tests TMT-B and CWIT 3. Shorter frontal, parietal, and occipital FBLs were associated with poorer performance on L-N Seq and Symbol Coding. Shorter frontal and temporal FBLs were associated with lower performance on CPS tests TMT-A and CWIT 1. Shorter FBLs were also associated with increased age. Results suggest an age-related FBL shortening in specific brain regions related to poorer EF and CPS performance among older adults. Overall, results support both the frontal aging hypothesis and processing speed theory, suggesting that each mechanism is contributing to age-related cognitive decline. © 2014, Springer Science+Business Media New York.

Author Keywords
Aging;  Cognitive processing speed;  DTI;  Executive function;  Fiber bundle lengths;  White matter

Document Type: Article
Source: Scopus

Kertz, S.J.a b , Belden, A.C.c , Tillman, R.c , Luby, J.c
Cognitive Control Deficits in Shifting and Inhibition in Preschool Age Children are Associated with Increased Depression and Anxiety Over 7.5 Years of Development
(2015) Journal of Abnormal Child Psychology, pp. 1-12. Article in Press. 

DOI: 10.1007/s10802-015-0101-0

a Department of Psychology, Southern Illinois University, Carbondale, IL, United States
b McLean Hospital, Behavioral Health Partial Program, Belmont, MA, United States
c Washington University School of Medicine, St. Louis, MO, United States

Although depression and anxiety are common in youth (Costello et al. 2003), factors that put children at risk for such symptoms are not well understood. The current study examined associations between early childhood cognitive control deficits and depression and anxiety over the course of development through school age. Participants were 188 children (at baseline M = 5.42 years, SD = 0.79 years) and their primary caregiver. Caregivers completed ratings of children’s executive functioning at preschool age and measures of depression and anxiety severity over seven assessment waves (a period of approximately 7.5 years). Longitudinal multilevel linear models were used to examine the effect of attention shifting and inhibition deficits on depression and anxiety. Inhibition deficits at preschool were associated with significantly greater depression severity scores at each subsequent assessment wave (up until 7.5 years later). Inhibition deficits were associated with greater anxiety severity from 3.5 to 7.5 years later. Greater shifting deficits at preschool age were associated with greater depression severity up to 5.5 years later. Shifting deficits were also associated with significantly greater anxiety severity up to 3.5 years later. Importantly, these effects were significant even after accounting for the influence of other key predictors including assessment wave/time, gender, parental education, IQ, and symptom severity at preschool age, suggesting that effects are robust. Overall, findings indicate that cognitive control deficits are an early vulnerability factor for developing affective symptoms. Timely assessment and intervention may be beneficial as an early prevention strategy. © 2015 Springer Science+Business Media New York

Author Keywords
Anxiety;  Cognitive control;  Depression;  Longitudinal;  Preschool

Document Type: Article in Press
Source: Scopus

Malanowski, S.
Is episodic memory uniquely human? Evaluating the episodic-like memory research program
(2015) Synthese, pp. 1-23. Article in Press. 

DOI: 10.1007/s11229-015-0966-z

Philosophy-Neuroscience-Psychology Program, The Department of Philosophy, Washington University in St. Louis, One Brookings Drive, St. Louis, MO, United States

Recently, a research program has emerged that aims to show that animals have a memory capacity that is similar to the human episodic memory capacity. Researchers within this program argue that nonhuman animals have episodic-like memory of personally experienced past events. In this paper, I specify and evaluate the goals of this research program and the progress it has made in achieving them. I will examine some of the data that the research program has produced, as well as the operational definitions and assumptions that have gone into producing that data, in order to call into question the ultimate value of the episodic-like memory research program. I argue that there is a gap between the claims that the research program makes and the data it uses to support these claims, and that bridging this gap is essential if we want to claim that human episodic memory has a meaningful analog in animals. I end with some suggestions of how to potentially fix these problems. © 2015 Springer Science+Business Media Dordrecht

Author Keywords
Comparative cognition;  Comparative psychology;  Episodic memory;  Episodic-like memory

Document Type: Article in Press
Source: Scopus

Farjam, R.a , Pramanik, P.b , Aryal, M.P.b , Srinivasan, A.c , Chapman, C.H.b , Tsien, C.I.d , Lawrence, T.S.b , Cao, Y.a b e
A radiation-induced hippocampal vascular injury surrogate marker predicts late neurocognitive dysfunction
(2015) International Journal of Radiation Oncology Biology Physics, 93 (4), pp. 908-915. 

DOI: 10.1016/j.ijrobp.2015.08.014

a Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, NY, United States
b Department of Radiation Oncology, University of Michigan, 519 W William St, Ann Arbor, MI, United States
c Department of Radiology, University of Michigan, Ann Arbor, MI, United States
d Department of Radiation Oncology, Washington University in St. Louis, St. Louis, MO, United States
e Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States

Purpose: We aimed to develop a hippocampal vascular injury surrogate marker for early prediction of late neurocognitive dysfunction in patients receiving brain radiation therapy (RT). Methods and Materials: Twenty-seven patients (17 males and 10 females, 31-80 years of age) were enrolled in an institutional review board-approved prospective longitudinal study. Patients received diagnoses of low-grade glioma or benign tumor and were treated by (3D) conformal or intensity-modulated RT with a median dose of 54 Gy (50.4-59.4 Gy in 1.8-Gy fractions). Six dynamic-contrast enhanced MRI scans were performed from pre-RT to 18-month post-RT, and quantified for vascular parameters related to blood-brain barrier permeability, Ktrans, and the fraction of blood plasma volume, Vp. The temporal changes in the means of hippocampal transfer constant Ktrans and Vp after starting RT were modeled by integrating the dose effects with age, sex, hippocampal laterality, and presence of tumor or edema near a hippocampus. Finally, the early vascular dose response in hippocampi was correlated with neurocognitive dysfunction at 6 and 18 months post-RT. Results: The mean Ktrans Increased significantly from pre-RT to 1-month post-RT (P<.0004), which significantly depended on sex (P<.0007) and age (P<.00004), with the dose response more pronounced in older females. Also, the vascular dose response in the left hippocampus of females correlated significantly with changes in memory function at 6 (rZ-0.95, P<.0006) and 18-months (rZ-0.88, P<.02) post-RT. Conclusions: The early hippocampal vascular dose response could be a predictor of late neurocognitive dysfunction. A personalized hippocampus sparing strategy may be considered in the future. © 2015 Elsevier Inc. All rights reserved.

Document Type: Article
Source: Scopus

Beebe, J.a , Qiaoan, R.b , Wysocki, T.c , Endara, M.A.d
Erratum: Moral Objectivism in Cross-Cultural Perspective (Journal of Cognition and Culture (2015) 15 (386-401) DOI:10.1163/15685373-12342157)
(2015) Journal of Cognition and Culture, 15 (5), pp. 543-544. 

DOI: 10.1163/15685373-12342165

a Department of Philosophy, State University of New York at Buffalo, 131 Park Hall, Buffalo, NY, United States
b Sun Yat-sen University, Kanton, China
c Department of Philosophy, Washington University in St. Louis, One Brookings Drive, St. Louis, MO, United States
d Azusa Pacific Online University, 901 E. Alosta Avenue, Azusa, CA, United States

Document Type: Erratum
Source: Scopus

Carr, D.B.a , O'Neill, D.b
Mobility and safety issues in drivers with dementia
(2015) International Psychogeriatrics, 27 (10), pp. 1613-1622. Cited 1 time.

DOI: 10.1017/S104161021500085X

a Division of Geriatrics and Nutritional Science, Department of Medicine and Neurology, Washington University in St. Louis, 660 Euclid Dr. St. LouisMO, United States
b Tallaght Hospital and Trinity College Dublin, Trinity Centre for Health Sciences, Tallaght Hospital, Dublin 24, Ireland

Although automobiles remain the mobility method of choice for older adults, late-life cognitive impairment and progressive dementia will eventually impair the ability to meet transport needs of many. There is, however, no commonly utilized method of assessing dementia severity in relation to driving, no consensus on the specific types of assessments that should be applied to older drivers with cognitive impairment, and no gold standard for determining driving fitness or approaching loss of mobility and subsequent counseling. Yet, clinicians are often called upon by patients, their families, health professionals, and driver licensing authorities to assess their patients' fitness-to-drive and to make recommendations about driving privileges. We summarize the literature on dementia and driving, discuss evidenced-based assessments of fitness-to-drive, and outline the important ethical and legal concerns. We address the role of physician assessment, referral to neuropsychology, functional screens, dementia severity tools, driving evaluation clinics, and driver licensing authority referrals that may assist clinicians with an evaluation. Finally, we discuss mobility counseling (e.g. exploration of transportation alternatives) since health professionals need to address this important issue for older adults who lose the ability to drive. The application of a comprehensive, interdisciplinary approach to the older driver with cognitive impairment will have the best opportunity to enhance our patients' social connectedness and quality of life, while meeting their psychological and medical needs and maintaining personal and public safety. © International Psychogeriatric Association 2015.

Author Keywords
Alzheimer's disease;  assessment;  automobile;  cognitive impairment;  dementia;  driving;  older adult;  transportation

Document Type: Review
Source: Scopus

Nayak, L.a , Deangelis, L.M.b , Robins, H.I.c , Govindan, R.d , Gadgeel, S.e , Kelly, K.f , Rigas, J.R.g , Peereboom, D.M.h , Rosenfeld, S.S.i l m , Muzikansky, A.j , Zheng, M.k , Urban, P.k , Abrey, L.E.b h , Omuro, A.b , Wen, P.Y.a
Multicenter phase 2 study of patupilone for recurrent or progressive brain metastases from non-small cell lung cancer
(2015) Cancer, 121 (23), pp. 4165-4172. 

DOI: 10.1002/cncr.29636

a Center For Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
b Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, United States
c Department of Human Oncology, University of Wisconsin Hospital and Clinics, Madison, WI, United States
d Division of Oncology, Washington University, School of Medicine in St. Louis, St. Louis, MO, United States
e Karmanos Cancer Institute, Wayne State University, Detroit, MI, United States
f Division of Hematology and Oncology, Davis Comprehensive Cancer Center, University of California, Sacramento, CA, United States
g Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
h Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH, United States
i Department of Neurology, Columbia University Medical Center/New York Presbyterian, New York, NY, United States
j Biostatistics Center, Massachusetts General Hospital, Boston, MA, United States
k Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States
l University of Zurich, Zurich, Switzerland
m F-Hoffman-La Roche, Ltd., Basel, Switzerland

BACKGROUND Treatment options for patients with non-small cell lung cancer (NSCLC) with brain metastases are limited. Patupilone (EPO906), a blood-brain barrier-penetrating, microtubule-targeting, cytotoxic agent, has shown clinical activity in phase 1/2 studies in patients with NSCLC. This study evaluates the efficacy, pharmacokinetics, and safety of patupilone in NSCLC brain metastases. METHODS Adult patients with NSCLC and confirmed progressive brain metastases received patupilone intravenously at 10 mg/m2 every 3 weeks. The primary endpoint of this multinomial 2-stage study combined early progression (EP; death or progression within 3 weeks) and progression-free survival at 9 weeks (PFS9w) to determine drug activity. RESULTS Fifty patients with a median age of 60 years (range, 33-74 years) were enrolled; the majority were men (58%), and most had received prior therapy for brain metastases (98%). The PFS9w rate was 36%, and the EP rate was 26%. Patupilone blood pharmacokinetic analyses showed mean areas under the concentration-time curve from time zero to 504 hours for cycles 1 and 3 of 1544 and 1978 ng h/mL, respectively, and a mean steady state distribution volume of 755 L/m2. Grade 3/4 adverse events (AEs), regardless of their relation with the study drug, included diarrhea (24%), pulmonary embolisms (8%), convulsions (4%), and peripheral neuropathy (4%). All patients discontinued the study drug: 31 (62%) for disease progression and 13 (26%) for AEs. Twenty-five of 32 deaths were due to brain metastases. The median time to progression and the overall survival were 3.2 and 8.8 months, respectively. CONCLUSIONS This is the first prospective study of chemotherapy for recurrent brain metastases from NSCLC. In this population, patupilone demonstrated activity in heavily treated patients. © 2015 American Cancer Society.

Author Keywords
brain metastases;  chemotherapy;  non-small cell lung cancer;  patupilone;  recurrent metastases

Document Type: Conference Paper
Source: Scopus

Kazmierczak, M.a , Harris, S.L.a , Kazmierczak, P.b , Shah, P.a , Starovoytov, V.a , Ohlemiller, K.K.c , Schwander, M.a
Progressive hearing loss in mice carrying a mutation in Usp53
(2015) Journal of Neuroscience, 35 (47), pp. 15582-15598. 

DOI: 10.1523/JNEUROSCI.1965-15.2015

a Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ, United States
b National Institute of Health and Medical Research, Unit 1051, Institute for Neurosciences of Montpellier, Montpellier, France
c Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, United States

Disordered protein ubiquitination has been linked to neurodegenerative disease, yet its role in inner ear homeostasis and hearing loss is essentially unknown. Here we show that progressive hearing loss in the ethylnitrosourea-generated mambo mouse line is caused by a mutation in Usp53, a member of the deubiquitinating enzyme family. USP53 contains a catalytically inactive ubiquitin-specific protease domain and is expressed in cochlear hair cells and a subset of supporting cells. Although hair cell differentiation is unaffected in mambo mice, outer hair cells degenerate rapidly after the first postnatal week. USP53 colocalizes and interacts with the tight junction scaffolding proteins TJP1 and TJP2 in polarized epithelial cells, suggesting that USP53 is part of the tight junction complex. The barrier properties of tight junctions of the stria vascularis appeared intact in a biotin tracer assay, but the endocochlear potential is reduced in adult mambo mice. Hair cell degeneration in mambo mice precedes endocochlear potential decline and is rescued in cochlear organotypic cultures in low potassium milieu, indicating that hair cell loss is triggered by extracellular factors. Remarkably, heterozygous mambo mice show increased susceptibility to noise injury at high frequencies. We conclude that USP53 is a novel tight junction-associated protein that is essential for the survival of auditory hair cells and normal hearing in mice, possibly by modulating the barrier properties and mechanical stability of tight junctions. © 2015 the authors.

Author Keywords
Hearing loss;  Inner ear;  Mambo mice;  Tight junction;  Ubiquitin;  Usp53

Document Type: Article
Source: Scopus

Ong, C.J.a , Yarbrough, C.K.b , Derdeyn, C.P.c
Response to letter regarding article, "Endovascular thrombectomy for anterior circulation stroke: Systematic review and meta-analysis"
(2015) Stroke, 46 (12), p. e259. 

DOI: 10.1161/STROKEAHA.115.011727

a Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
b Department of Neurological Surgery, Washington University, School of Medicine, St. Louis, MO, United States
c Mallinckrodt Institute of Radiology, Washington University, School of Medicine, St. Louis, MO, United States

Document Type: Letter
Source: Scopus

Tang, Y.-Y.a , Tang, R.b
Rethinking Future Directions of the Mindfulness Field
(2015) Psychological Inquiry, 26 (4), pp. 368-372. 

DOI: 10.1080/1047840X.2015.1075850

a Department of Psychological Sciences, Texas Tech University, Lubbock, TX, United States
b Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States


Document Type: Note
Source: Scopus