WashU weekly Neuroscience publications

Regeneration associated transcriptional signature of retinal microglia and macrophages
(2019) Scientific Reports, 9 (1), art. no. 4768, . 

Mitchell, D.M.^a , Sun, C.^{a b} , Hunter, S.S.^c , New, D.D.^c , Stenkamp, D.L.^a

^a Department of Biological Sciences, University of Idaho, Moscow, ID 83844, United States
^b Ophthalmology, Washington University in St. Louis, 4523 Clayton Ave St. LouisMO 63110, United States
^c Institute for Bioinformatics and Evolutionary Studies, University of Idaho, Moscow, ID 83844, United States

Abstract
Zebrafish have the remarkable capacity to regenerate retinal neurons following a variety of damage paradigms. Following initial tissue insult and a period of cell death, a proliferative phase ensues that generates neuronal progenitors, which ultimately regenerate damaged neurons. Recent work has revealed that Müller glia are the source of regenerated neurons in zebrafish. However, the roles of another important class of glia present in the retina, microglia, during this regenerative phase remain elusive. Here, we examine retinal tissue and perform QuantSeq. 3′mRNA sequencing/transcriptome analysis to reveal localization and putative functions, respectively, of mpeg1 expressing cells (microglia/macrophages) during Müller glia-mediated regeneration, corresponding to a time of progenitor proliferation and production of new neurons. Our results indicate that in this regenerative state, mpeg1-expressing cells are located in regions containing regenerative Müller glia and are likely engaged in active vesicle trafficking. Further, mpeg1+ cells congregate at and around the optic nerve head. Our transcriptome analysis reveals several novel genes not previously described in microglia. This dataset represents the first report, to our knowledge, to use RNA sequencing to probe the microglial transcriptome in such context, and therefore provides a resource towards understanding microglia/macrophage function during successful retinal (and central nervous tissue) regeneration. © 2019, The Author(s).

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

CHD4 regulates the DNA damage response and RAD51 expression in glioblastoma
(2019) Scientific Reports, 9 (1), art. no. 4444, . 

McKenzie, L.D.^a , LeClair, J.W.^a , Miller, K.N.^a , Strong, A.D.^a , Chan, H.L.^a , Oates, E.L.^a , Ligon, K.L.^b , Brennan, C.W.^c , Chheda, M.G.^{a d}

^a Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston Children’s Hospital, and Dana Farber Cancer Institute, Boston, MA, United States
^c Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States
^d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Glioblastoma (GBM) is a lethal brain tumour. Despite therapy with surgery, radiation, and alkylating chemotherapy, most people have recurrence within 6 months and die within 2 years. A major reason for recurrence is resistance to DNA damage. Here, we demonstrate that CHD4, an ATPase and member of the nucleosome remodelling and deactetylase (NuRD) complex, drives a component of this resistance. CHD4 is overexpressed in GBM specimens and cell lines. Based on The Cancer Genome Atlas and Rembrandt datasets, CHD4 expression is associated with poor prognosis in patients. While it has been known in other cancers that CHD4 goes to sites of DNA damage, we found CHD4 also regulates expression of RAD51, an essential component of the homologous recombination machinery, which repairs DNA damage. Correspondingly, CHD4 suppression results in defective DNA damage response in GBM cells. These findings demonstrate a mechanism by which CHD4 promotes GBM cell survival after DNA damaging treatments. Additionally, we found that CHD4 suppression, even in the absence of extrinsic treatment, cumulatively increases DNA damage. Lastly, we found that CHD4 is dispensable for normal human astrocyte survival. Since standard GBM treatments like radiation and temozolomide chemotherapy create DNA damage, these findings suggest an important resistance mechanism that has therapeutic implications. © 2019, The Author(s).

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

Social networks and risk of delayed hospital arrival after acute stroke
(2019) Nature Communications, 10 (1), art. no. 1206, . 

Dhand, A.^{a b} , Luke, D.^c , Lang, C.^d , Tsiaklides, M.^e , Feske, S.^a , Lee, J.-M.^e

^a Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, United States
^b Network Science Institute, Northeastern University, Boston, MA 02115, United States
^c Center for Public Health Systems Science, Washington University in St. Louis, St. Louis, MO 63130, United States
^d Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO 63108, United States
^e Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Arriving rapidly to the hospital after a heart attack or stroke is critical for patients to be within time windows for treatment. Prior research in heart attacks has suggested a paradoxical role of the social environment: those who arrive early are surrounded by nonrelatives, while those who arrive late are surrounded by spouses or family members. Here, we used network methods to more deeply examine the influence of social context in stroke. We examined the relationship of personal social networks and arrival time in 175 stroke patients. Our results confirmed the paradox by showing that small and close-knit personal networks of highly familiar contacts, independent of demographic, clinical, and socioeconomic factors, were related to delay. The closed network structure led to constricted information flow in which patients and close confidants, absent outside perspectives, elected to watch-and-wait. Targeting patients with small, close-knit networks may be one strategy to improve response times. © 2019, The Author(s).

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

Cognitive Change After Cardiac Surgery Versus Cardiac Catheterization: A Population-Based Study
(2019) Annals of Thoracic Surgery, 107 (4), pp. 1119-1125. 

Whitlock, E.L.^a , Diaz-Ramirez, L.G.^b , Smith, A.K.^b , Boscardin, W.J.^{b c} , Avidan, M.S.^d , Glymour, M.M.^c

^a Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA, United States
^b Division of Geriatrics, Department of Medicine, University of California San Francisco, San Francisco, CA, United States
^c Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, United States
^d Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: Despite concern that cardiac surgery may adversely affect cognition, little evidence is available from population-based studies using presurgery data. With the use of the Health and Retirement Study, we compared memory change after participant-reported cardiac catheterization or cardiac surgery. Methods: Participants were community-dwelling adults aged 65 years and older who self-reported cardiac catheterization or “heart surgery” at any biennial Health and Retirement Study interview between 2000 and 2014. Participants may have undergone the index procedure any time in the preceding 2 years. We modeled preprocedure to postprocedure change in composite memory score, derived from objective memory testing, using linear mixed effects models. We modeled postprocedure subjective memory decline with logistic regression. To quantify clinical relevance, we used the predicted memory change to estimate impact on ability to manage medications and finances independently. Results: Of 3,105 participants, 1,921 (62%) underwent catheterization and 1,184 (38%) underwent operation. In adjusted analyses, surgery participants had little difference in preprocedure to postprocedure memory change compared with participants undergoing cardiac catheterization (−0.021 memory units; 95% confidence interval: −0.046 to 0.005 memory units, p = 0.12). If the relationship were causal, the point estimate for memory decline would confer an absolute 0.26% or 0.19% decrease in ability to manage finances or medications, respectively, corresponding to 4.6 additional months of cognitive aging. Cardiac surgery was not associated with subjective memory decline (adjusted odds ratio 0.93, 95% confidence interval: 0.74 to 1.18). Conclusions: In this large, population-based cohort, memory declines after heart surgery and cardiac catheterization were similar. These findings suggest intermediate-term population-level adverse cognitive effects of cardiac surgery, if any, are likely subtle. © 2019 The Society of Thoracic Surgeons

Document Type: Article
Publication Stage: Final
Source: Scopus

Sex differences in functional connectivity during fetal brain development
(2019) Developmental Cognitive Neuroscience, 36, art. no. 100632, . 

Wheelock, M.D.^a , Hect, J.L.^b , Hernandez-Andrade, E.^{d e} , Hassan, S.S.^{d e f} , Romero, R.^{c d g h i} , Eggebrecht, A.T.^j , Thomason, M.E.^{b d k}

^a Department of Psychiatry, Washington University in St. Louis, St. Louis, United States
^b Merrill Palmer Skillman Institute for Child and Family Development, Wayne State University, Detroit, United States
^c Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD 20847, United States
^d Perinatology Research Branch, NICHD/NIH/DHHS, Detroit, MI 48201, United States
^e Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI 48202, United States
^f Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48202, United States
^g Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI 48104, United States
^h Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI 48825, United States
ⁱ Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, United States
^j Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, United States
^k Institute for Social Research, University of Michigan, Ann Arbor, MI 48109, United States

Abstract
Sex-related differences in brain and behavior are apparent across the life course, but the exact set of processes that guide their emergence in utero remains a topic of vigorous scientific inquiry. Here, we evaluate sex and gestational age (GA)-related change in functional connectivity (FC) within and between brain wide networks. Using resting-state functional magnetic resonance imaging we examined FC in 118 human fetuses between 25.9 and 39.6 weeks GA (70 male; 48 female). Infomap was applied to the functional connectome to identify discrete prenatal brain networks in utero. A consensus procedure produced an optimal model comprised of 16 distinct fetal neural networks distributed throughout the cortex and subcortical regions. We used enrichment analysis to assess network-level clustering of strong FC-GA correlations separately in each sex group, and to identify network pairs exhibiting distinct patterns of GA-related change in FC between males and females. We discovered both within and between network FC-GA associations that varied with sex. Specifically, associations between GA and posterior cingulate-temporal pole and fronto-cerebellar FC were observed in females only, whereas the association between GA and increased intracerebellar FC was stronger in males. These observations confirm that sexual dimorphism in functional brain systems emerges during human gestation. © 2019

Author Keywords
Connectivity;  Gestational age;  MRI;  Prenatal;  Resting-state;  Sex

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

Emergent Functional Network Effects in Parkinson Disease
(2019) Cerebral cortex (New York, N.Y. : 1991), 29 (4), p. 1701. 

Gratton, C.^a , Koller, J.M.^b , Shannon, W.^c , Greene, D.J.^{b d} , Maiti, B.^a , Snyder, A.Z.^{a d} , Petersen, S.E.^{a d e f g h} , Perlmutter, J.S.^{a d f i j} , Campbell, M.C.^{a d}

^a Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
^c BioRankings, St. Louis, MO, United States
^d Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
^e Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States
^f Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
^g Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
^h Department of Neurological Surgery, Washington University in St. Louis, St. Louis, MO, United States
ⁱ Department of Occupational Therapy, Washington University in St. Louis, St. Louis, MO, United States
^j Department of Physical Therapy, Washington University in St. Louis, St. Louis, MO, United States

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

Glioblastoma Treated With Magnetic Resonance Imaging-Guided Laser Interstitial Thermal Therapy: Safety, Efficacy, and Outcomes
(2019) Neurosurgery, 84 (4), pp. 836-843. 

Kamath, A.A.^a , Friedman, D.D.^a , Akbari, S.H.A.^a , Kim, A.H.^{a b c d} , Tao, Y.^e , Luo, J.^{e f} , Leuthardt, E.C.^{a d g h i j k}

^a Departments of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
^d Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States
^g Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO, United States
^h Department of Mechanical Engineering and Materials Science, Washington University School of Medicine, St. Louis, MO, United States
ⁱ Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
^j Center for Innovation in Neuroscience and Technology, Washington University School of Medicine, St. Louis, MO, United States
^k Brain Laser Center, Washington University School of Medicine, St. Louis, MO, United States

Abstract
BACKGROUND: Despite the multitude of available treatments, glioblastoma (GBM) remains an aggressive and uniformly fatal tumor. Laser interstitial thermal therapy (LITT) is a novel, minimally invasive treatment that holds promise for treating patients with GBM who are not candidates for traditional open craniotomy. However, due to the recent introduction of LITT into clinical practice, large series that evaluate safety and long-term outcomes after LITT are lacking. OBJECTIVE: To present our institution’s series of over 50 GBM patients treated with LITT, with regard to safety, efficacy, and outcomes. METHODS: We performed a retrospective descriptive study of patients with histologically proven GBM who underwent LITT. Data collected included demographics, tumor location and volume, tumor genetic markers, treatment volume, perioperative complications, and long-term follow-up data. RESULTS: We performed 58 LITT treatments for GBM in 54 patients over 5.5 yr. Forty-one were recurrent tumors while 17 were frontline treatments. Forty GBMs were lobar in location, while 18 were in deep structures (thalamus, insula, corpus callosum). Average tumor volume was 12.5 ± 13.4 cm3. Average percentage of tumor treated with the yellow thermal damage threshold (TDT) line (dose equivalent of 43°C for 2 min) was 93.3% ± 10.6%, and with the blue TDT line (dose equivalent of 43°C for 10 min) was 88.0% ± 14.2%. There were 7 perioperative complications (12%) and 2 mortalities (3.4%). Median overall survival after LITT for the total cohort was 11.5 mo, and median progression-free survival 6.6 mo. CONCLUSION: LITT appears to be a safe and effective treatment for GBM in properly selected patients. © Congress of Neurological Surgeons 2018.

Author Keywords
Brain tumors;  GBM;  Glioblastoma;  Laser ablation;  Laser interstitial thermal therapy;  LITT;  MRI;  Thermoablation

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

Plasmapheresis for Management of Antiphospholipid Syndrome in the Neurosurgical Patient
(2019) Operative neurosurgery (Hagerstown, Md.), 16 (4), pp. E124-E129. 

Arias, E.J.^a , Bruck, B.^a , Vellimana, A.K.^a , Eby, C.^b , Reynolds, M.R.^c , Blinder, M.A.^d , Zipfel, G.J.^{a e}

^a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Neurological Surgery, Emory University School of Medicine, Atlanta, Georgia, France
^d Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
BACKGROUND AND IMPORTANCE: Antiphospholipid syndrome (APS) is an autoimmune disorder associated with a hypercoagulable state and increased risk of intraoperative and postoperative thrombosis. Few neurosurgical studies have examined the management of these patients, though the standard of care in most other disciplines involves the use of anticoagulation therapy. However, this is associated with risks such as hemorrhage, thrombosis due to warfarin withdrawal, and is not compatible with operative intervention. CLINICAL PRESENTATION: We report the cases of 2 antiphospholipid positive patients who were on anticoagulant therapy and underwent surgical bypasses and received perioperative management with plasmapheresis. The first was a 44-yr-old woman who presented with worsening vision, recurring headaches, and a known left internal carotid artery aneurysm that was unsuccessfully treated twice via extracranial to intracranial (ECIC) bypass at another institution. Preoperative tests at our institution revealed elevated beta 2 glycoprotein 1 IgA autoantibodies. The second case was a 24-yr-old woman with previously diagnosed APS, who presented for surgical evaluation of moyamoya disease after sustaining recurrent left hemispheric strokes. Both cases were managed with perioperative plasmapheresis to avoid the need for anticoagulation during the perioperative period, and both underwent successful ECIC bypass procedures without perioperative ischemic or hemorrhagic complications. CONCLUSION: Management of neurosurgical patients with APS can be a precarious proposition. We describe the successful use of plasmapheresis and antiplatelet therapy to better manage patients undergoing neurosurgical procedures, specifically ECIC bypass, and feel this approach can be considered in future cases. Copyright © 2018 by the Congress of Neurological Surgeons.

Author Keywords
Antiphospholipid syndrome;  Bypass;  Plasmapheresis

Document Type: Article
Publication Stage: Final
Source: Scopus

Late Morbidity and Mortality Among Medulloblastoma Survivors Diagnosed Across Three Decades: A Report From the Childhood Cancer Survivor Study
(2019) Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 37 (9), pp. 731-740. 

Salloum, R.^a , Chen, Y.^b , Yasui, Y.^{b c} , Packer, R.^d , Leisenring, W.^e , Wells, E.^d , King, A.^f , Howell, R.^g , Gibson, T.M.^c , Krull, K.R.^c , Robison, L.L.^c , Oeffinger, K.C.^h , Fouladi, M.^a , Armstrong, G.T.^c

^a 1 Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
^b University of Alberta, Edmonton, AB, Canada
^c St. Jude Children’s Research Hospital, Memphis, TN, United States
^d Children’s National Health SystemWA, United States
^e Fred Hutchinson Cancer Research Center, Seattle, WA, United States
^f Washington University in St Louis, St Louis, MO, United States
^g The University of Texas MD Anderson Cancer Center, Houston, TX, United States
^h Duke University, Durham, NC, United States

Abstract
PURPOSE: Treatment of medulloblastoma has evolved from surgery and radiotherapy to contemporary multimodal regimens. However, the impact on long-term health outcomes remains unknown. METHODS: Cumulative incidence of late mortality (5 or more years from diagnosis), subsequent neoplasms (SNs), and chronic health conditions were evaluated in the Childhood Cancer Survivor Study among 5-year survivors of medulloblastoma diagnosed between 1970 and 1999. Outcomes were evaluated by treatment exposure, including historical therapy (craniospinal irradiation [CSI] ≥ 30 Gy, no chemotherapy), high risk (CSI ≥ 30 Gy + chemotherapy), standard risk (CSI < 30 Gy + chemotherapy), and by treatment decade (1970s, 1980s, 1990s). Rate ratios (RRs) and 95% CIs estimated long-term outcomes using multivariable piecewise exponential models. RESULTS: Among 1,311 eligible survivors (median age, 29 years [range, 6 to 60 years]; median time from diagnosis, 21 years [range, 5 to 44 years]), the 15-year cumulative incidence rate of all-cause late mortality was 23.2% (diagnosed 1970s) versus 12.8% (1990s; P = .002), with a recurrence-related mortality rate of 17.7% versus 9.6% ( P = .008). Lower late mortality rates as a result of other health-related causes were not observed. Among 997 survivors who completed a baseline survey, the 15-year cumulative incidence of SNs was higher among survivors with multimodal therapy (standard risk, 9.5%; historical, 2.8%; P = .03). Survivors treated in the 1990s had a higher cumulative incidence of severe, disabling, life-threatening, and fatal chronic health conditions (56.5% in 1990s v 39.9% in 1970s; P < .001) and were more likely to develop multiple conditions (RR, 2.89; 95% CI, 1.31 to 6.38). However, survivors of standard-risk therapy were less likely to use special education services than high-risk therapy survivors (RR, 0.84; 95% CI, 0.75 to 0.93). CONCLUSION: Historical changes in medulloblastoma therapy that improved 5-year survival have increased the risk for SNs and debilitating health conditions for survivors yet reduced the need for special education services.

Document Type: Article
Publication Stage: Final
Source: Scopus

Network meta-analysis of randomised trials of pharmacological, psychotherapeutic, exercise and collaborative care interventions for depressive symptoms in patients with coronary artery disease: Hybrid systematic review of systematic reviews protocol
(2019) Systematic Reviews, 8 (1), art. no. 71, . 

Doyle, F.^{a b} , Freedland, K.^c , Carney, R.^c , De Jonge, P.^d , Dickens, C.^e , Pedersen, S.^f , Sorensen, J.^g , Dempster, M.^h

^a Department of Health Psychology, Royal College of Surgeons in Ireland, 123 St Stephen’s Green, Dublin 2, Ireland
^b School of Psychology, Queen’s University Belfast, University Road, Belfast, BT71NN, United Kingdom
^c Washington University, School of Medicine, St. Louis, United States
^d University of Groningen, Groningen, Netherlands
^e University of Exeter, Exeter, United Kingdom
^f University of Southern Denmark, Odense, Denmark
^g Royal College of Surgeons in Ireland, Dublin, Ireland
^h Queen’s University Belfast, Belfast, United Kingdom

Abstract
Background: Depression is common in patients with coronary artery disease (CAD) and is associated with poorer outcomes and higher costs. Several randomised controlled trials (RCTs) targeting depression, of various modalities (including pharmacological, psychotherapeutic and other approaches), have been conducted and summarised in pairwise meta-analytic reviews. However, no study has considered the cumulative evidence within a network, which can provide valuable indirect comparisons and information about the relative efficacy of interventions. Therefore, we will adopt a review of review methodology to develop a network meta-analysis (NMA) of depression interventions for depression in CAD. Methods: We will search relevant databases from inception for systematic reviews of RCTs of depression treatments for people with CAD, supplementing this with comprehensive searches for recent or ongoing studies. We will extract data from and summarise characteristics of individual RCTs, including participants, study characteristics, outcome measures and adverse events. Cochrane risk of bias ratings will also be extracted or if not present will be conducted by the authors. RCTs that compare depression treatments (grouped as pharmacological, psychotherapeutic, combined pharmacological/psychotherapeutic, exercise, collaborative care) to placebo, usual care, waitlist control or attention controls, or directly in head-to-head comparisons, will be included. Primary outcomes will be the change in depressive symptoms (summarised with a standardised mean difference) and treatment acceptability (treatment discontinuation: % of people who withdrew). Secondary outcomes will include change in 6-month depression outcomes, health-related quality of life (HRQoL), mortality, cardiovascular morbidity, health services use and adverse events. Secondary analyses will form further networks with individual anti-depressants and psychotherapies. We will use frequentist, random effects multivariate network meta-analysis to synthesise the evidence for depression intervention and to achieve a ranking of treatments, using Stata. Rankograms and surface under the cumulative ranking curves will be used for treatment ranking. Local and global methods will evaluate consistency. GRADE will be used to assess evidence quality for primary outcomes. Discussion: The present review will address uncertainties about the evidence in terms of depression management in CAD and may allow for a ranking of treatments, including providing important information for future research efforts. © 2019 The Author(s).

Author Keywords
Coronary artery disease;  Depression;  Intervention;  Network meta-analysis;  Randomised controlled trial;  Systematic review

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

Context before implementation: a qualitative study of decision makers’ views of a peer-led healthy lifestyle intervention for people with serious mental illness in supportive housing
(2019) Translational behavioral medicine, 9 (2), pp. 217-226. 

Cabassa, L.J.^a , Stefancic, A.^b

^a George Warren Brown School of Social Work, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA

Abstract
People with serious mental illness die at an earlier age than people in the general population largely due to cardiovascular disease. Healthy lifestyle interventions can help reduce this health inequity. In this qualitative study, we examined the perceptions that decision makers in supportive housing agencies had toward a peer-led healthy lifestyle intervention and their views of contextual factors that could shape implementation at these agencies. A purposive sample of 12 decision makers from three supportive housing agencies was recruited. We presented participants a vignette describing our peer-led intervention and used semistructured qualitative interviews to examine their views. Interviews were recorded, professionally transcribed, and analyzed using directed content analysis. Participants reported positive views toward the intervention with the most valued intervention attributes being relative advantage over existing services, compatibility to clients’ needs, ability to pilot the intervention, and cost. A model emerged from our data depicting multilevel contextual factors believed to shape the implementation of our intervention at these agencies, including system- (funding, marketability, and external regulations), organization- (leadership support, fit with organization, staff buy-in and burden), and client-level (adaptability to clients’ needs, and clients’ buy-in) factors. Study findings illustrate the importance of understanding the context of practice before implementation. This examination can help identify critical views from decision makers that could undermine or advance the integration of peer-led interventions in supportive housing agencies and help identify structures, policies, and organizational practices that can inform the implementation process. © Society of Behavioral Medicine 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
Healthy lifestyle interventions;  Implementation context;  Obesity;  Serious mental illness;  Supportive housing

Document Type: Article
Publication Stage: Final
Source: Scopus

Organization of extrastriate and temporal cortex in chimpanzees compared to humans and macaques
(2019) Cortex, . 

Bryant, K.L.^{a b} , Glasser, M.F.^c , Li, L.^d , Jae-Cheol Bae, J.^{e f} , Jacquez, N.J.^e , Alarcón, L.^e , Fields, A., III^g , Preuss, T.M.^{a h i}

^a Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Emory University, Atlanta, GA, United States
^b Donders Institute for Brain, Cognition, and Behaviour, Radboud University, Nijmegen, Netherlands
^c Departments of Radiology and Neuroscience, Washington University Medical School, St. Louis, MO, United States
^d Marcus Autism Center, Children’s Healthcare of Atlanta, Emory University, Atlanta, GA, United States
^e Neuroscience and Behavioral Biology, Emory University, Atlanta, GA, United States
^f College of Medicine, American University of Antigua, United States
^g Department of Philosophy, University of Calgary, Calgary, Alberta, Canada
^h Center for Translational Social Neuroscience, Emory University, Atlanta, GA, United States
ⁱ Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, United States

Abstract
There is evidence for enlargement of association cortex in humans compared to other primate species. Expansion of temporal association cortex appears to have displaced extrastriate cortex posteriorly and inferiorly in humans compared to macaques. However, the details of the organization of these recently expanded areas are still being uncovered. Here, we used diffusion tractography to examine the organization of extrastriate and temporal association cortex in chimpanzees, humans, and macaques. Our goal was to characterize the organization of visual and auditory association areas with respect to their corresponding primary areas (primary visual cortex and auditory core) in humans and chimpanzees. We report three results: (1) Humans, chimpanzees, and macaques show expected retinotopic organization of primary visual cortex (V1) connectivity to V2 and to areas immediately anterior to V2; (2) In contrast to macaques, chimpanzee and human V1 shows apparent connectivity with lateral, inferior, and anterior temporal regions, beyond the retinotopically organized extrastriate areas; (3) Also in contrast to macaques, chimpanzee and human auditory core shows apparent connectivity with temporal association areas, with some important differences between humans and chimpanzees. Diffusion tractography reconstructs diffusion patterns that reflect white matter organization, but does not definitively represent direct anatomical connectivity. Therefore, it is important to recognize that our findings are suggestive of species differences in long-distance white matter organization rather than demonstrations of direct connections. Our data support the conclusion that expansion of temporal association cortex, and the resulting posterior displacement of extrastriate cortex, occurred in the human lineage after its separation from the chimpanzee lineage. It is possible, however, that some expansion of the temporal lobe occurred prior to the separation of humans and chimpanzees, reflected in the reorganization of long white matter tracts in the temporal lobe that connect occipital areas to the fusiform gyrus, middle temporal gyrus, and anterior temporal lobe. © 2019 Elsevier Ltd

Author Keywords
Auditory cortex;  Diffusion;  Evolution;  Tractography;  Visual cortex

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

Neurocognitive SuperAging in Older Adults Living with HIV: Demographic, Neuromedical and Everyday Functioning Correlates
(2019) Journal of the International Neuropsychological Society, . 

Saloner, R.^{a b} , Campbell, L.M.^{a b} , Serrano, V.^b , Montoya, J.L.^b , Pasipanodya, E.^b , Paolillo, E.W.^{a b} , Franklin, D.^b , Ellis, R.J.^b , Letendre, S.L.^c , Collier, A.C.^d , Clifford, D.B.^e , Gelman, B.B.^f , Marra, C.M.^g , McCutchan, J.A.^c , Morgello, S.^h , Sacktor, N.ⁱ , Jeste, D.V.^{b j} , Grant, I.^b , Heaton, R.K.^b , Moore, D.J.^b

^a San Diego State University, University of California, San Diego Joint Doctoral Program in Clinical Psychology, San Diego, CA, United States
^b Department of Psychiatry, University of California, San Diego, San Diego, CA, United States
^c Department of Medicine, University of California, San Diego, San Diego, CA, United States
^d Department of Medicine, University of Washington, Seattle, WA, United States
^e Department of Neurology, Washington University, St. Louis, MO, United States
^f Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States
^g Department of Neurology, University of Washington, Seattle, WA, United States
^h Department of Neurology, Icahn School of Medicine of Mount Sinai, New York, NY, United States
ⁱ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^j Stein Institute for Research on Aging, University of California, San Diego, San Diego, CA, United States

Abstract
Objectives: Studies of neurocognitively elite older adults, termed SuperAgers, have identified clinical predictors and neurobiological indicators of resilience against age-related neurocognitive decline. Despite rising rates of older persons living with HIV (PLWH), SuperAging (SA) in PLWH remains undefined. We aimed to establish neuropsychological criteria for SA in PLWH and examined clinically relevant correlates of SA. Methods: 734 PLWH and 123 HIV-uninfected participants between 50 and 64 years of age underwent neuropsychological and neuromedical evaluations. SA was defined as demographically corrected (i.e., sex, race/ethnicity, education) global neurocognitive performance within normal range for 25-year-olds. Remaining participants were labeled cognitively normal (CN) or impaired (CI) based on actual age. Chi-square and analysis of variance tests examined HIV group differences on neurocognitive status and demographics. Within PLWH, neurocognitive status differences were tested on HIV disease characteristics, medical comorbidities, and everyday functioning. Multinomial logistic regression explored independent predictors of neurocognitive status. Results: Neurocognitive status rates and demographic characteristics differed between PLWH (SA=17%; CN=38%; CI=45%) and HIV-uninfected participants (SA=35%; CN=55%; CI=11%). In PLWH, neurocognitive groups were comparable on demographic and HIV disease characteristics. Younger age, higher verbal IQ, absence of diabetes, fewer depressive symptoms, and lifetime cannabis use disorder increased likelihood of SA. SA reported increased independence in everyday functioning, employment, and health-related quality of life than non-SA. Conclusions: Despite combined neurological risk of aging and HIV, youthful neurocognitive performance is possible for older PLWH. SA relates to improved real-world functioning and may be better explained by cognitive reserve and maintenance of cardiometabolic and mental health than HIV disease severity. Future research investigating biomarker and lifestyle (e.g., physical activity) correlates of SA may help identify modifiable neuroprotective factors against HIV-related neurobiological aging. Copyright © The International Neuropsychological Society 2019.

Author Keywords
Acquired Immunodeficiency Syndrome;  Cannabis;  Cognitive decline;  Cognitive reserve;  Diabetes;  Neuropsychology

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

The BDNF Val66Met SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer’s disease
(2019) Molecular Psychiatry, . 

Franzmeier, N.^a , Ren, J.^a , Damm, A.^a , Monté-Rubio, G.^b , Boada, M.^{b c} , Ruiz, A.^{b c} , Ramirez, A.^{d e} , Jessen, F.^{d f} , Düzel, E.^g , Rodríguez Gómez, O.^{b c} , Benzinger, T.^{h i} , Goate, A.^{j k} , Karch, C.M.^{i l m} , Fagan, A.M.^{i l n} , McDade, E.ⁿ , Buerger, K.^{a o} , Levin, J.^{o p} , Duering, M.^a , Dichgans, M.^{a o q} , Suárez-Calvet, M.^{o r s} , Haass, C.^{o s} , Gordon, B.A.^{i t u} , Lim, Y.Y.^v , Masters, C.L.^v , Janowitz, D.^a , Catak, C.^a , Wolfsgruber, S.^{e f} , Wagner, M.^{e f} , Milz, E.^d , Moreno-Grau, S.^{b c} , Teipel, S.^{w x} , Grothe, M.J.^w , Kilimann, I.^w , Rossor, M.^y , Fox, N.^y , Laske, C.^{z aa} , Chhatwal, J.^ab , Falkai, P.^ac , Perneczky, R.^{o q ac ad} , Lee, J.-H.^ae , Spottke, A.^{f af} , Boecker, H.^{f ag} , Brosseron, F.^{e f} , Fliessbach, K.^{e f} , Heneka, M.T.^{e f} , Nestor, P.^{g ah} , Peters, O.^{ai aj} , Fuentes, M.^{ai aj} , Menne, F.^{ai aj} , Priller, J.^{ai ak} , Spruth, E.J.^{ai ak} , Franke, C.^{ai ak} , Schneider, A.^{e f} , Westerteicher, C.^{e f} , Speck, O.^{g al am an} , Wiltfang, J.^{ao ap aq} , Bartels, C.^ap , Araque Caballero, M.Á.^{a o} , Metzger, C.^g , Bittner, D.^g , Salloway, S.^ar , Danek, A.^p , Hassenstab, J.ⁿ , Yakushev, I.^as , Schofield, P.R.^{at au} , Morris, J.C.^{i m n} , Bateman, R.J.^{i n} , Ewers, M.^a

^a Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany
^b Fundació ACE, Alzheimer Treatment and Research Center, Barcelona, Spain
^c CIBERNED, Center for Networked Biomedical Research on Neurodegenerative Diseases, National Institute of Health Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain
^d Department of Psychiatry, Medical Faculty, University of Cologne, Cologne, Germany
^e Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn, Bonn, Germany
^f German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
^g German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany
^h Department of Radiology, Washington University in St Louis, St Louis, MO, United States
ⁱ Knight Alzheimer’s Disease Research Center, Washington University in St. Louis, St. Louis, MO, United States
^j Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^k Ronald M. Loeb Center for Alzheimer’s Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^l Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO, United States
^m Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States
ⁿ Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^o German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
^p Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
^q Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
^r Barcelonabeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Catalonia, Spain
^s Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany
^t Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO, United States
^u Department of Psychological and Brain Sciences, Washington University, St. Louis, MO, United States
^v The Florey Institute, The University of Melbourne, Parkville, VIC, Australia
^w German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany
^x Department of Psychosomatic Medicine, University Hospital Rostock, Rostock, Germany
^y Dementia Research Centre, University College London, Queen Square, London, United Kingdom
^z Hertie Institute for Clinical Brain Research, Tübingen, Germany
^aa Germany and German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
^ab Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Boston, MA, United States
^ac Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-Universität München, Munich, Germany
^ad Neuroepidemiology and Ageing Research Unit, School of Public Health, The Imperial College of Science, Technology and Medicine, London, United Kingdom
^ae Department of Neurology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
^af Department of Neurology, University of Bonn, Bonn, Germany
^ag Department of Radiology, University of Bonn, Bonn, Germany
^ah Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia
^ai German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany
^aj Department of Psychiatry and Psychotherapy, Charité, Berlin, Germany
^ak Department of Neuropsychiatry, Charité, Berlin, Germany
^al Leibniz Institute for Neurobiology, Magdeburg, Germany
^am Center for Behavioral Brain Sciences, Magdeburg, Germany
^an Department for Biomedical Magnetic Resonance, Institute for Physics, Otto-von-Guericke University, Magdeburg, Germany
^ao German Center for Neurodegenerative Diseases (DZNE), Goettingen, Germany
^ap Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, University of Goettingen, Goettingen, Germany
^aq iBiMED, Medical Sciences Department, University of Aveiro, Aveiro, Portugal
^ar Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI, United States
^as Department of Nuclear Medicine, Technical University of Munich, Munich, Germany
^at Neuroscience Research Australia, Barker Street Randwick, Sydney, NSW 2031, Australia
^au School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia

Abstract
In Alzheimer’s disease (AD), a single-nucleotide polymorphism in the gene encoding brain-derived neurotrophic factor (BDNF Val66Met ) is associated with worse impact of primary AD pathology (beta-amyloid, Aβ) on neurodegeneration and cognitive decline, rendering BDNF Val66Met an important modulating factor of cognitive impairment in AD. However, the effect of BDNF Val66Met on functional networks that may underlie cognitive impairment in AD is poorly understood. Using a cross-validation approach, we first explored in subjects with autosomal dominant AD (ADAD) from the Dominantly Inherited Alzheimer Network (DIAN) the effect of BDNF Val66Met on resting-state fMRI assessed functional networks. In seed-based connectivity analysis of six major large-scale networks, we found a stronger decrease of hippocampus (seed) to medial-frontal connectivity in the BDNF Val66Met carriers compared to BDNF Val homozogytes. BDNF Val66Met was not associated with connectivity in any other networks. Next, we tested whether the finding of more pronounced decrease in hippocampal-medial-frontal connectivity in BDNF Val66Met could be also found in elderly subjects with sporadically occurring Aβ, including a group with subjective cognitive decline (N = 149, FACEHBI study) and a group ranging from preclinical to AD dementia (N = 114, DELCODE study). In both of these independently recruited groups, BDNF Val66Met was associated with a stronger effect of more abnormal Aβ-levels (assessed by biofluid-assay or amyloid-PET) on hippocampal-medial-frontal connectivity decreases, controlled for hippocampus volume and other confounds. Lower hippocampal-medial-frontal connectivity was associated with lower global cognitive performance in the DIAN and DELCODE studies. Together these results suggest that BDNF Val66Met is selectively associated with a higher vulnerability of hippocampus-frontal connectivity to primary AD pathology, resulting in greater AD-related cognitive impairment. © 2019, Springer Nature Limited.

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

NRG brain tumor specialists consensus guidelines for glioblastoma contouring
(2019) Journal of Neuro-Oncology, . 

Kruser, T.J.^a , Bosch, W.R.^b , Badiyan, S.N.^b , Bovi, J.A.^c , Ghia, A.J.^d , Kim, M.M.^e , Solanki, A.A.^f , Sachdev, S.^a , Tsien, C.^b , Wang, T.J.C.^g , Mehta, M.P.^h , McMullen, K.P.ⁱ

^a Department of Radiation Oncology, Northwestern Memorial Hospital, 251 E Huron St, LC-178, Galter Pavilion, Chicago, IL 60611, United States
^b Department of Radiation Oncology, Washington University, St. Louis, MO, United States
^c Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, United States
^d Department of Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX, United States
^e Department of Radiation Oncology, University of Michigan Hospital, Ann Arbor, MI, United States
^f Department of Radiation Oncology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, United States
^g Department of Radiation Oncology, Columbia University Medical Center, New York, NY, United States
^h Miami Cancer Institute, Miami, FL, United States
ⁱ Columbus Regional Health, Columbus, IN, United States

Abstract
Introduction: NRG protocols for glioblastoma allow for clinical target volume (CTV) reductions at natural barriers; however, literature examining CTV contouring and the relevant white matter pathways is lacking. This study proposes consensus CTV guidelines, with a focus on areas of controversy while highlighting common errors in glioblastoma target delineation. Methods: Ten academic radiation oncologists specializing in brain tumor treatment contoured CTVs on four glioblastoma cases. CTV expansions were based on NRG trial guidelines. Contour consensus was assessed and summarized by kappa statistics. A meeting was held to discuss the mathematically averaged contours and form consensus contours and recommendations. Results: Contours of the cavity plus enhancement (mean kappa 0.69) and T2-FLAIR signal (mean kappa 0.74) showed moderate to substantial agreement. Experts were asked to trim off anatomic barriers while respecting pathways of spread to develop their CTVs. Submitted CTV_4600 (mean kappa 0.80) and CTV_6000 (mean kappa 0.81) contours showed substantial to near perfect agreement. Simultaneous truth and performance level estimation (STAPLE) contours were then reviewed and modified by group consensus. Anatomic trimming reduced the amount of total brain tissue planned for radiation targeting by a 13.6% (range 8.7–17.9%) mean proportional reduction. Areas for close scrutiny of target delineation were described, with accompanying recommendations. Conclusions: Consensus contouring guidelines were established based on expert contours. Careful delineation of anatomic pathways and barriers to spread can spare radiation to uninvolved tissue without compromising target coverage. Further study is necessary to accurately define optimal target volumes beyond isometric expansion techniques for individual patients. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Clinical target volume;  Consensus;  Contouring;  Glioblastoma

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

Feasibility, Acceptability, and Initial Efficacy of Delivering Alcohol Use Cognitive Interventions via Crowdsourcing
(2019) Alcoholism: Clinical and Experimental Research, . 

Strickland, J.C.^a , Hill, J.C.^b , Stoops, W.W.^{a c d e} , Rush, C.R.^{a c d}

^a Department of Psychology, University of Kentucky College of Arts and Sciences, Lexington, KY, United States
^b Department of Mathematics and Statistics, Washington University in St. Louis College of Arts and Sciences, St. Louis, MO, United States
^c Department of Behavioral Science, University of Kentucky College of Medicine, Lexington, KY, United States
^d Department of Psychiatry, University of Kentucky College of Medicine, Lexington, KY, United States
^e Center on Drug and Alcohol Research, University of Kentucky College of Medicine, Lexington, KY, United States

Abstract
Background: Inhibitory control training and working memory training are 2 cognitive interventions that have been considered for alcohol use disorder (AUD). Existing studies have typically relied on small samples that preclude the evaluation of small effects. Crowdsourcing is a sampling method that can address these limitations by effectively and efficiently recruiting large samples with varying health histories. This study tested the feasibility and acceptability of delivering cognitive training interventions via crowdsourcing. Methods: Participants with AUD were recruited from the crowdsourcing website Amazon Mechanical Turk (mTurk) (ClinicalTrials.gov; NCT03438539). Following completion of a baseline survey, participants were randomized to an inhibitory control, working memory, or control training condition. Participants were asked to complete training tasks daily over a 2-week period. Follow-up assessments evaluating acceptability measures and alcohol and soda consumption were completed immediately following and 2 weeks after training. Results: Response rates were satisfactory over the 2-week intervention period (65% of training tasks completed), and performance on training tasks was consistent with expected effects. A majority of participants indicated that they were satisfied with the study procedures (94.6%), would participate again (97.4%), and would consider incorporating the training task in their daily life (81.1%). Modest reductions in alcohol consumption were observed (e.g., 0.5 drinking day/wk), primarily in the inhibitory control group, and these effects were selective to alcohol use and did not extend to soda consumption. Conclusions: These findings demonstrate the feasibility and acceptability of utilizing crowdsourcing methods for interventions development. Such a demonstration helps establish the crowdsourcing setting for future large sample studies testing novel interventions for AUD and other substance use disorders. © 2019 by the Research Society on Alcoholism

Author Keywords
Alcohol;  Crowdsourcing;  Inhibitory Control;  mTurk;  Working Memory

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

Quantification of white matter cellularity and damage in preclinical and early symptomatic Alzheimer’s disease
(2019) NeuroImage: Clinical, 22, art. no. 101767, . 

Wang, Q.^{a b} , Wang, Y.^{a b c d e} , Liu, J.^f , Sutphen, C.L.^{b e g} , Cruchaga, C.^{e h} , Blazey, T.ⁱ , Gordon, B.A.^{a b} , Su, Y.^j , Chen, C.^a , Shimony, J.S.^a , Ances, B.M.^{a b e g} , Cairns, N.J.^{b k} , Fagan, A.M.^{b e g} , Morris, J.C.^{b g} , Benzinger, T.L.S.^{a b l}

^a Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Knight Alzheimer’s Disease Research Center, 4488 Forest Park, Suite 101, St. Louis, MO 63108, United States
^c Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Department of Biomedical Engineering, Washington University School of Engineering & Applied Science, St. Louis, MO 63015, United States
^e Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States
^f Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, United States
^g Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
^h Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
ⁱ Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, United States
^j Banner Alzheimer’s Institute, Phoenix, AZ 85006, United States
^k Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States
^l Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Interest in understanding the roles of white matter (WM) inflammation and damage in the pathophysiology of Alzheimer disease (AD) has been growing significantly in recent years. However, in vivo magnetic resonance imaging (MRI) techniques for imaging inflammation are still lacking. An advanced diffusion-based MRI method, neuro-inflammation imaging (NII), has been developed to clinically image and quantify WM inflammation and damage in AD. Here, we employed NII measures in conjunction with cerebrospinal fluid (CSF) biomarker classification (for β-amyloid (Aβ) and neurodegeneration) to evaluate 200 participants in an ongoing study of memory and aging. Elevated NII-derived cellular diffusivity was observed in both preclinical and early symptomatic phases of AD, while disruption of WM integrity, as detected by decreased fractional anisotropy (FA) and increased radial diffusivity (RD), was only observed in the symptomatic phase of AD. This may suggest that WM inflammation occurs earlier than WM damage following abnormal Aβ accumulation in AD. The negative correlation between NII-derived cellular diffusivity and CSF Aβ 42 level (a marker of amyloidosis) may indicate that WM inflammation is associated with increasing Aβ burden. NII-derived FA also negatively correlated with CSF t-tau level (a marker of neurodegeneration), suggesting that disruption of WM integrity is associated with increasing neurodegeneration. Our findings demonstrated the capability of NII to simultaneously image and quantify WM cellularity changes and damage in preclinical and early symptomatic AD. NII may serve as a clinically feasible imaging tool to study the individual and composite roles of WM inflammation and damage in AD. © 2019 The Authors

Author Keywords
Cerebrospinal fluid;  Diffusion basis spectrum imaging;  Early symptomatic Alzheimer disease;  Inflammation;  Magnetic resonance imaging;  Neuro-inflammation imaging;  Preclinical Alzheimer disease;  White matter damage

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

Ready for the Challenge of Depression Care in the Medical Home
(2019) Clinical Pediatrics, . 

Garbutt, J., Sterkel, R., Ruecker, K., Dodd, S., Smith, E., Plax, K.

Washington University, St. Louis, MO, United States

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

A pilot digital intervention targeting loneliness in young people with psychosis
(2019) Social Psychiatry and Psychiatric Epidemiology, . 

Lim, M.H.^{a b} , Gleeson, J.F.M.^c , Rodebaugh, T.L.^d , Eres, R.^{a b} , Long, K.M.^a , Casey, K.^b , Abbott, J.-A.M.^e , Thomas, N.^b , Penn, D.L.^{c f}

^a Iverson Health Innovation Research Institute, Swinburne University of Technology, Hawthorn, Melbourne, 3122, Australia
^b Centre for Mental Health, Swinburne University of Technology, Hawthorn, Melbourne, 3122, Australia
^c School of Behavioural and Health Sciences, Australian Catholic University, Sydney, Australia
^d Department of Psychological and Brain Sciences, Washington University in St Louis, St. Louis, United States
^e Australian Psychological Society, Melbourne, Australia
^f Department of Psychology and Neuroscience, University of North Carolina Chapel Hill, Chapel Hill, United States

Abstract
Purpose: Loneliness has been identified as a significant challenge for people with psychosis. Interventions targeting loneliness are lacking but adopting a positive psychology approach may reduce loneliness, promote well-being, and support meaningful social interactions. Together with youth mental health consumers, we developed a digital smartphone application (app) called +Connect, which delivers positive psychology content daily for 6 weeks. Materials and methods: Twelve participants diagnosed with a psychotic disorder were recruited from early psychosis services. Loneliness was assessed pre-intervention, post-intervention, and 3-month post-intervention. Acceptability, feasibility, and usability were measured post-intervention, including a semi-structured interview on the user’s experience of +Connect. Results: We found evidence for the feasibility of +Connect. All but two participants completed the +Connect program, completing 95% (40.10 out of 42 days) of the program. Furthermore, 66.67% (8 out of the 12 participants) remained engaged with the program 3-months post-intervention. Our data indicates preliminary evidence that +Connect may reduce loneliness, with scores from pre-intervention (M = 50.00, SD = 8.47) to post-intervention (M = 48.10, SD = 10.38) and 3-months post-intervention (M = 42.89, SD = 7.04). We found that positive reinforcement of in-game rewards and evidence of positive mood changes added to the feasibility of the app. Regarding acceptability, while 10% (1/10 participants) reported not finding +Connect useful or enjoyable, 90% of participants agreed that +Connect helped them to increase their social confidence, enjoy life, look forward to being with other people, and feel more connected with others. Participant interviews supported these results, with participants highlighting the app’s strengths in providing useful information, stimulating self-reflection, fostering positive affect, and encouraging transfer of skills into their social interactions. Discussion: While preliminary findings indicated that +Connect yielded high levels of acceptability and feasibility, it is important to consider that we recruited a small and selected sample of lonely young people. Further iterations of this proof of concept app, which can incorporate participant feedback such preferences for increased personalisation, in-app feedback, and gamification, may allow an opportunity to test an improved version in the future. © 2019, Springer-Verlag GmbH Germany, part of Springer Nature.

Author Keywords
Digital intervention;  Loneliness;  Positive psychology intervention;  Psychosis

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

Progressive multifocal leukoencephalopathy treated with nivolumab
(2019) Journal of NeuroVirology, . 

Hoang, E.^a , Bartlett, N.L.^b , Goyal, M.S.^{a c} , Schmidt, R.E.^d , Clifford, D.B.^a

^a Department of Neurology, Washington University in St. Louis, Box 8111, 660 South Euclid Avenue, Saint Louis, MO 63110, United States
^b Department of Medicine, 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 Pathology and Immunology, Washington University in St. Louis, St Louis, MO, United States

Abstract
Therapy for progressive multifocal leukoencephalopathy (PML) remains challenging since there are no antiviral therapies available for JC virus. Immune reconstitution has improved the prognosis in many settings where PML occurs, but it often is not possible in PML patients with hematologic malignancies. We describe the first biopsy proven PML case where the PD-1 inhibitor nivolumab appears to have stimulated immune activation resulting in effective control of PML in a patient with hematologic malignancy. This report supports further investigation of the utility of checkpoint inhibitors for treating PML where other immune reconstitution options are not available. © 2019, Journal of NeuroVirology, Inc.

Author Keywords
JC virus;  Nivolumab;  PD-1 inhibitor;  PML;  Progressive multifocal leukoencephalopathy

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

Mood regulation and relationship quality predict change in homesickness during college
(2019) British Journal of Psychology, . 

Landa, I., Bono, T.J., English, T.

Department of Psychological and Brain Sciences, Washington University in St. LouisMO, United States

Abstract
Recent theorizing has implicated affect regulation as central to the experience of homesickness. Conceptualized as grief due to losing social connections with close others when relocating, homesickness is associated with poor emotional and social adjustment. The present study examined how mood regulation and relationship quality – at home and in college – predict homesickness and negative affect among college students (N = 168). We assessed 16 mood regulation strategies as well as relationship quality each week over the first college term. As predicted, time-lagged multilevel analyses demonstrate that avoidance-oriented strategies were helpful in the short term (the following week), but chronic avoidance (across the college term) predicted higher levels of homesickness. Approach-oriented regulatory strategies did not predict homesickness, however. Relationship quality demonstrated differential main effects at the between-person level but did not predict fluctuations in homesickness from week to week. Across the college term, closer ties at home predicted greater homesickness, whereas closer ties in college predicted lower homesickness. Notably, there were distinct effects of mood regulation for homesickness compared to negative affect. The present study is among the first to examine effects of mood regulation on homesickness longitudinally, suggesting it is important to consider the type of regulation strategies being used as well as the time scale. © 2019 The British Psychological Society

Author Keywords
approach;  avoidance;  homesickness;  mood regulation;  relationship quality

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

Fronto-striatal activity predicts anhedonia and positive empathy subtypes
(2019) Brain Imaging and Behavior, . 

Mirabito, G.^a , Taiwo, Z.^b , Bezdek, M.^c , Light, S.N.^{d e}

^a Neuroscience Institute, Georgia State University, 100 Piedmont Ave SE, Atlanta, GA 30303, United States
^b Department of Psychology, Georgia State University, 140 Decatur Street, Atlanta, GA 30303, United States
^c Dynamic Cognition Laboratory, Washington University in St. Louis, Campus Box 1125, One Brookings Drive, St. Louis, MO 63130, United States
^d Positive Affective Neuroscience Laboratory, Department of Psychology, Georgia State University, 140 Decatur Street, Atlanta, GA 30303, United States
^e Center for Advanced Brain Imaging (CABI), 831 Marietta St NW, Atlanta, GA 30318, United States

Abstract
The dorsolateral prefrontal cortex, globus pallidus, and nucleus accumbens are important components of the reward circuit in the brain; and prior research suggests individuals with damage to these regions feel less pleasure (i.e., are anhedonic). However, little is known about how these brain regions relate to vicarious pleasure. Pilot fMRI data were collected from 20 participants (M age = 22, SD = 7.0, 63% female) during a validated empathy induction paradigm that utilized video clips extracted from the television show “Extreme Makeover: Home Edition” to elicit empathic happiness (i.e. vicarious happiness) when targets display positive affect, and either empathic cheerfulness (i.e. the tendency to want to cheer someone up) or empathic concern (i.e. vicarious sadness) when targets display negative affect. Participants also completed the novel “Happy Faces” task—a behavioral measure of anhedonia—while fMRI was collected. fMRI data during task completion were used to predict trait empathy measured via self-report outside of the scanner, and accuracy on the “Happy Faces” task. Results indicate that globus pallidus activity during empathic concern-eliciting video clips significantly predicted self-reported trait empathic cheerfulness (R 2 = 26%, p = 0.045). Furthermore, greater dorsolateral prefrontal cortex (DLPFC) activity during the Happy Faces task predicted accurate performance on the task (R 2 = 34%, p &lt;.05); and greater nucleus accumbens shell activity during the Happy Faces task predicted greater trait empathic happiness (R 2 = 38%, p &lt;.05). These results suggest that fronto-striatal circuitry contributes to our experience of anhedonia, empathic happiness, and empathic cheerfulness. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Anhedonia;  fMRI;  Positive empathy

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

Impact of overall corticosteroid exposure during chemoradiotherapy on lymphopenia and survival of glioblastoma patients
(2019) Journal of Neuro-Oncology, . 

Hui, C.Y.^a , Rudra, S.^b , Ma, S.^b , Campian, J.L.^c , Huang, J.^b

^a Saint Louis University School of Medicine, Saint Louis, MO 63104, United States
^b Department of Radiation Oncology, Washington University School of Medicine, 4921 Parkview Place, Campus Box 8224, St. Louis, MO 63110, United States
^c Division of Oncology, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Purpose: Corticosteroids are commonly used to alleviate symptoms from cerebral vasogenic edema in glioblastoma (GBM) patients. This study evaluated the impact of overall corticosteroid exposure during chemoradiotherapy (CRT) on acute severe lymphopenia (ASL) and survival outcomes of GBM patients. Methods: GBM patients treated with CRT from 2007 to 2016 were retrospectively analyzed. Overall corticosteroid exposure was estimated as the average daily dexamethasone dose during 6 weeks of CRT. ASL was defined as grade 3 or higher lymphopenia within 3 months of starting CRT. ASL rates, overall survival (OS), and progression-free survival (PFS) were analyzed using Kaplan–Meier method. Multivariable analysis (MVA) was performed using logistic and Cox regression to identify independent predictors of ASL and survival outcomes, respectively. Results: Of the 319 eligible patients, the median daily dexamethasone use was 2 mg/day. The high-dose dexamethasone cohort (> 2 mg/day) had significantly higher ASL and worse OS than the low-dose dexamethasone cohort: 3-month ASL of 43.7% versus 19.8% (p < 0.003) and median OS of 12.6 months versus 17.9 months (p < 0.001), respectively. On MVA, higher dexamethasone use was independently associated with higher ASL and worse OS, but not worse PFS. A subset analysis of patients with gross-total resection found that higher dexamethasone use was significantly associated with ASL, but not OS. Conclusion: Increased corticosteroid use among GBM patients during CRT appears to be an independent risk factor for developing subsequent ASL. Its apparent association with worse OS may be influenced by other confounding factors and would need to be validated through prospective investigations. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Chemoradiotherapy;  Corticosteroids;  Glioblastoma;  Lymphopenia

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

Cornelia de Lange syndrome, related disorders, and the Cohesin complex: Abstracts from the 8th biennial scientific and educational symposium 2018
(2019) American Journal of Medical Genetics, Part A, . 

Kline, A.D.^a , Krantz, I.D.^{b c} , Bando, M.^d , Shirahige, K.^d , Chea, S.^e , Sakata, T.^d , Rao, S.^f , Dorsett, D.^g , Singh, V.P.^h , Gerton, J.L.^h , Horsfield, J.A.ⁱ , Calof, A.L.^e , Katz, O.^b , Grados, M.^j , Raible, S.^b , Barañano, K.^k , Lyon, G.^l , Musio, A.^m , Carrico, C.S.ⁿ , Clemens, D.K.^o , Caudill, P.^p , Massa, V.^q , McGill, B.E.^r , Dommestrup, A.^s , O’Connor, J.^s , Haaland, R.E.^t

^a Department of Pediatrics, Greater Baltimore Medical Center, Harvey Institute for Human Genetics, Baltimore, United States
^b Division of Human Genetics, The Children’s Hospital of Philadelphia, United States
^c Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA, United States
^d Laboratory of Genome Structure and Function, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan
^e Departments of Anatomy & Neurobiology, Developmental and Cell Biology, and the Center for Complex Biological Systems, University of California, Irvine, CA, United States
^f Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, United States
^g Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO, United States
^h Stowers Institute for Medical Research, and Department of Biochemistry and Molecular Biology, University of Kansas School of Medicine, Kansas City, MO, United States
ⁱ Department of Pathology, Dunedin School of Medicine, The University of Otago, Dunedin, New Zealand
^j Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, United States
^k Child Neurology and Developmental Medicine, Johns Hopkins University School of Medicine, Baltimore, United States
^l Cold Spring Harbor Laboratory, Cold Spring HarborNY, United States
^m Institute for Genetic and Biologic Research, National Research Council, Pisa, Italy
ⁿ Communication Sciences and Disorders, Elmhurst College, Elmhurst, IL, United States
^o Department of Oral Maxillofacial Surgery and Dentistry, Sinai Hospital of Baltimore, and Cross Keys Dental Associates, Baltimore, MD, United States
^p Milton J. Dance, Jr. Head & Neck Center, Greater Baltimore Medical Center, Baltimore, MD, United States
^q Department of Health Sciences, University of Milan, Milan, Italy
^r Division of Pediatric and Developmental Neurology, Department of Neurology, Washington University, St. Louis, MO, United States
^s Kennedy Krieger Institute, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^t Research Department, Cornelia de Lange Syndrome Foundation, Avon, CT, United States

Abstract
Cornelia de Lange Syndrome (CdLS), due to mutations in genes of the cohesin protein complex, is described as a disorder of transcriptional regulation. Phenotypes in this expanding field include short stature, microcephaly, intellectual disability, variable facial features and organ involvement, resulting in overlapping presentations, including established syndromes and newly described conditions. Individuals with all forms of CdLS have multifaceted complications, including neurodevelopmental, feeding, craniofacial, and communication. Coping mechanisms and management of challenging behaviors in CdLS, disruption of normal behaviors, and how behavior molds the life of the individual within the family is now better understood. Some psychotropic medications are known to be effective for behavior. Other medications, for example, Indomethacin, are being investigated for effects on gene expression, fetal brain tissue, brain morphology and function in Drosophila, mice, and human fibroblasts containing CdLS-related mutations. Developmental studies have clarified the origin of cardiac defects and role of placenta in CdLS. Chromosome architecture and cohesin complex structure are elucidated, leading to a better understanding of regulatory aspects and controls. As examples, when mutations are present, the formation of loop domains by cohesin, facilitating enhancer-promotor interactions, can be eliminated, and embryologically, the nuclear structure of zygotes is disrupted. Several important genes are now known to interact with cohesin, including Brca2. The following abstracts are from the 8th Cornelia de Lange Syndrome Scientific and Educational Symposium, held in June 2018, Minneapolis, MN, before the CdLS Foundation National Meeting, AMA CME credits provided by GBMC, Baltimore, MD. All studies have been approved by an ethics committee. © 2019 Wiley Periodicals, Inc.

Author Keywords
behavior;  CdLS;  cohesin complex;  de Lange syndrome;  loop domains;  transcription regulation

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

Age-specific associations between oestradiol, cortico-amygdalar structural covariance, and verbal and spatial skills
(2019) Journal of Neuroendocrinology, art. no. e12698, . 

Nguyen, T.-V.^{a b c} , Jones, S.L.^{d e} , Gower, T.^d , Lew, J.^d , Albaugh, M.D.^f , Botteron, K.N.^{g h} , Hudziak, J.J.^{f h} , Fonov, V.S.ⁱ , Louis Collins, D.ⁱ , Campbell, B.C.^j , Booij, L.^{a k l} , Herba, C.M.^{l m} , Monnier, P.^{b c} , Ducharme, S.^{a i n} , Waber, D.^o , McCracken, J.T.^{h p}

^a Department of Psychiatry, McGill University, Montreal, QC, Canada
^b Department of Obstetrics-Gynecology, McGill University Health Center, Montreal, QC, Canada
^c Research Institute of the McGill University Health Center, Montreal, QC, Canada
^d Department of Psychology, McGill University, Montreal, QC, Canada
^e Douglas Mental Health University Institute, Verdun, QC, Canada
^f Department of Psychology, University of Vermont, College of Medicine, Burlington, VT, Canada
^g Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
^h Brain Development Cooperative Group, United States
ⁱ McConnell Brain imaging Centre, Montreal Neurological Institute, Montreal, QC, Canada
^j Department of Anthropology, University of Wisconsin-Milwaukee, Milwaukee, WI, United States
^k Department of Psychology, Concordia University, Montreal, QC, Canada
^l CHU Sainte Justine Hospital Research Centre, University of Montreal, Montreal, QC, Canada
^m Department of Psychology, Université du Québec à Montréal, Montreal, QC, Canada
ⁿ Department of Neurology & Neurosurgery, McGill University, Montreal, QC, Canada
^o Department of Psychiatry, Harvard Medical School, Boston, MA, United States
^p Department of Child and Adolescent Psychiatry, University of California in Los Angeles, Los Angeles, CA, United States

Abstract
Oestradiol is known to play an important role in the developing human brain, although little is known about the entire network of potential regions that might be affected and how these effects may vary from childhood to early adulthood, which in turn can explain sexually differentiated behaviours. In the present study, we examined the relationships between oestradiol, cortico-amygdalar structural covariance, and cognitive or behavioural measures typically showing sex differences (verbal/spatial skills, anxious-depressed symptomatology) in 152 children and adolescents (aged 6-22 years). Cortico-amygdalar structural covariance shifted from positive to negative across the age range. Oestradiol was found to diminish the impact of age on cortico-amygdalar covariance for the pre-supplementary motor area/frontal eye field and retrosplenial cortex (across the age range), as well as for the posterior cingulate cortex (in older children). Moreover, the influence of oestradiol on age-related cortico-amygdalar networks was associated with higher word identification and spatial working memory (across the age range), as well as higher reading comprehension (in older children), although it did not impact anxious-depressed symptoms. There were no significant sex effects on any of the above relationships. These findings confirm the importance of developmental timing on oestradiol-related effects and hint at the non-sexually dimorphic role of oestradiol-related cortico-amygdalar structural networks in aspects of cognition distinct from emotional processes. © 2019 British Society for Neuroendocrinology

Author Keywords
adolescence;  cognition;  oestrogen;  puberty;  structural covariance

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