Arts & Sciences Brown School McKelvey School of Engineering School of Law School of Medicine Weekly Publications

WashU weekly Neuroscience publications

“Quantification of brain oxygen extraction and metabolism with (15O)-gas PET: A technical review in the era of PET-MRI” (2020) NeuroImage

Quantification of brain oxygen extraction and metabolism with [15O]-gas PET: A technical review in the era of PET/MRI
(2020) NeuroImage, 220, art. no. 117136, . 

Fan, A.P.a b , An, H.c , Moradi, F.a , Rosenberg, J.a , Ishii, Y.a d , Nariai, T.d , Okazawa, H.e , Zaharchuk, G.a

a Department of Radiology, Stanford University, Stanford, CA, United States
b Department of Biomedical Engineering and Department of Neurology, University of California Davis, Davis, CA, United States
c Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
d Department of Neurosurgery, Tokyo Medical and Dental University, Tokyo, Japan
e Biomedical Imaging Research Center, University of Fukui, Fukui, Japan

Abstract
Oxygen extraction fraction (OEF) and the cerebral metabolic rate of oxygen (CMRO2) are key cerebral physiological parameters to identify at-risk cerebrovascular patients and understand brain health and function. PET imaging with [15O]-oxygen tracers, either through continuous or bolus inhalation, provides non-invasive assessment of OEF and CMRO2. Numerous tracer delivery, PET acquisition, and kinetic modeling approaches have been adopted to map brain oxygenation. The purpose of this technical review is to critically evaluate different methods for [15O]-gas PET and its impact on the accuracy and reproducibility of OEF and CMRO2 measurements. We perform a meta-analysis of brain oxygenation PET studies in healthy volunteers and compare between continuous and bolus inhalation techniques. We also describe OEF metrics that have been used to detect hemodynamic impairment in cerebrovascular disease. For these patients, advanced techniques to accelerate the PET scans and potential synthesis with MRI to avoid arterial blood sampling would facilitate broader use of [15O]-oxygen PET for brain physiological assessment. © 2020 The Author(s)

Author Keywords
Cerebral metabolic rate of oxygen;  Oxygen extraction fraction;  Positron emission tomography;  [15O]-oxygen

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

“SARM1 acts downstream of neuroinflammatory and necroptotic signaling to induce axon degeneration” (2020) The Journal of Cell Biology

SARM1 acts downstream of neuroinflammatory and necroptotic signaling to induce axon degeneration
(2020) The Journal of Cell Biology, 219 (8), . 

Ko, K.W.a , Milbrandt, J.b c , DiAntonio, A.a c

a Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO
b Department of Genetics, Washington University School of Medicine, St. Louis, MO
c Needleman Center for Neurometabolism and Axonal Therapeutics, Washington University School of Medicine, St. Louis, MO

Abstract
Neuroinflammation and necroptosis are major contributors to neurodegenerative disease, and axon dysfunction and degeneration is often an initiating event. SARM1 is the central executioner of pathological axon degeneration. Here, we demonstrate functional and mechanistic links among these three pro-degenerative processes. In a neuroinflammatory model of glaucoma, TNF-α induces SARM1-dependent axon degeneration, oligodendrocyte loss, and subsequent retinal ganglion cell death. TNF-α also triggers SARM1-dependent axon degeneration in sensory neurons via a noncanonical necroptotic signaling mechanism. MLKL is the final executioner of canonical necroptosis; however, in axonal necroptosis, MLKL does not directly trigger degeneration. Instead, MLKL induces loss of the axon survival factors NMNAT2 and STMN2 to activate SARM1 NADase activity, which leads to calcium influx and axon degeneration. Hence, these findings define a specialized form of axonal necroptosis. The demonstration that neuroinflammatory signals and necroptosis can act locally in the axon to stimulate SARM1-dependent axon degeneration identifies a therapeutically targetable mechanism by which neuroinflammation can stimulate axon loss in neurodegenerative disease. © 2020 Ko et al.

Document Type: Article
Publication Stage: Final
Source: Scopus

“The chromatin remodeling enzyme Chd4 regulates genome architecture in the mouse brain” (2020) Nature Communications

The chromatin remodeling enzyme Chd4 regulates genome architecture in the mouse brain
(2020) Nature Communications, 11 (1), p. 3419. 

Goodman, J.V.a b , Yamada, T.a c d , Yang, Y.a d , Kong, L.a , Wu, D.Y.a , Zhao, G.a , Gabel, H.W.a , Bonni, A.a

a Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, USA
b Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO, USA
c Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
d Department of Neurobiology, Northwestern University, Evanston, United States

Abstract
The development and function of the brain require tight control of gene expression. Genome architecture is thought to play a critical regulatory role in gene expression, but the mechanisms governing genome architecture in the brain in vivo remain poorly understood. Here, we report that conditional knockout of the chromatin remodeling enzyme Chd4 in granule neurons of the mouse cerebellum increases accessibility of gene regulatory sites genome-wide in vivo. Conditional knockout of Chd4 promotes recruitment of the architectural protein complex cohesin preferentially to gene enhancers in granule neurons in vivo. Importantly, in vivo profiling of genome architecture reveals that conditional knockout of Chd4 strengthens interactions among developmentally repressed contact domains as well as genomic loops in a manner that tightly correlates with increased accessibility, enhancer activity, and cohesin occupancy at these sites. Collectively, our findings define a role for chromatin remodeling in the control of genome architecture organization in the mammalian brain.

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

“Variation in the strength of allometry drives rates of evolution in primate brain shape” (2020) Proceedings. Biological Sciences

Variation in the strength of allometry drives rates of evolution in primate brain shape
(2020) Proceedings. Biological Sciences, 287 (1930), p. 20200807.

Sansalone, G.a , Allen, K.b c , Ledogar, J.A.d , Ledogar, S.a e , Mitchell, D.R.a f , Profico, A.g , Castiglione, S.h , Melchionna, M.h , Serio, C.h i , Mondanaro, A.h j , Raia, P.h , Wroe, S.a

a Function, Evolution and Anatomy Research Lab, Zoology Division, School of Environmental and Rural Science, University of New England, Armidale, NSW 2351, Australia
b Department of Neuroscience, Washington University School of Medicine in St Louis, MO, United States
c Department of Anthropology, Washington University in St Louis, MO, WA, United States
d Department of Evolutionary Anthropology, Duke University, Durham, NC 27708, United States
e Department of Archaeology and Palaeoanthropology, School of Humanities, University of New England, Armidale, NSW 2351, Australia
f Department of Anthropology, University of Arkansas, Old Main 330, Fayetteville, United States
g Dipartimento di Biologia Ambientale, Sapienza Università di Roma, Roma, Italy
h Department of Earth Sciences, Environment and Resources, Università degli Studi di Napoli Federico II, L.go San Marcellino 10, Naples, 80138, Italy
i Research Centre in Evolutionary Anthropology and Palaeoecology, School of Biological and Environmental Sciences, Liverpool John Moores University, Liverpool, United Kingdom
j Department of Earth Sciences, University of Florence, Italy

Abstract
Large brains are a defining feature of primates, as is a clear allometric trend between body mass and brain size. However, important questions on the macroevolution of brain shape in primates remain unanswered. Here we address two: (i), does the relationship between the brain size and its shape follow allometric trends and (ii), is this relationship consistent over evolutionary time? We employ three-dimensional geometric morphometrics and phylogenetic comparative methods to answer these questions, based on a large sample representing 151 species and most primate families. We found two distinct trends regarding the relationship between brain shape and brain size. Hominoidea and Cercopithecinae showed significant evolutionary allometry, whereas no allometric trends were discernible for Strepsirrhini, Colobinae or Platyrrhini. Furthermore, we found that in the taxa characterized by significant allometry, brain shape evolution accelerated, whereas for taxa in which such allometry was absent, the evolution of brain shape decelerated. We conclude that although primates in general are typically described as large-brained, strong allometric effects on brain shape are largely confined to the order’s representatives that display more complex behavioural repertoires.

Author Keywords
allometry;  brain shape;  evolutionary rates;  geometric morphometrics;  phylogenetic comparative methods;  primates

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

“Photoacoustic topography through an ergodic relay for functional imaging and biometric application in vivo” (2020) Journal of Biomedical Optics

Photoacoustic topography through an ergodic relay for functional imaging and biometric application in vivo
(2020) Journal of Biomedical Optics, 25 (7), pp. 1-8. 

Li, Y.a b c , Li, L.a b , Zhu, L.a b c , Shi, J.a b , Maslov, K.a , Wang, L.V.a b

a California Institute of Technology, Caltech Optical Imaging Laboratory, United States
b California Institute of Technology, Department of Electrical Engineering, Pasadena, CA, United States
c Washington University in St. Louis, Department of Biomedical Engineering, St. Louis, MO, United States

Abstract
SIGNIFICANCE: Photoacoustic (PA) tomography has demonstrated versatile biomedical applications. However, an array-based PA computed tomography (PACT) system is complex and expensive, whereas a single-element detector-based scanning PA system is too slow to detect some fast biological dynamics in vivo. New PA imaging methods are sought after. AIM: To overcome these limitations, we developed photoacoustic topography through an ergodic relay (PATER), a novel high-speed imaging system with a single-element detector. APPROACH: PATER images widefield PA signals encoded by the acoustic ergodic relay with a single-laser shot. RESULTS: We applied PATER in vivo to monitor changes in oxygen saturation in a mouse brain and also to demonstrate high-speed matching of vascular patterns for biometric authentication. CONCLUSIONS: PATER has achieved a high-speed temporal resolution over a large field of view. Our results suggest that PATER is a promising and economical alternative to PACT for fast imaging.

Author Keywords
biomedical optics;  imaging systems;  photoacoustics

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

“Participatory Design of a Personalized Genetic Risk Tool to Promote Behavioral Health” (2020) Cancer Prevention Research (Philadelphia, Pa.)

Participatory Design of a Personalized Genetic Risk Tool to Promote Behavioral Health
(2020) Cancer Prevention Research (Philadelphia, Pa.), 13 (7), pp. 583-592. 

Ramsey, A.T.a , Bray, M.a , Acayo Laker, P.b , Bourdon, J.L.a , Dorsey, A.a , Zalik, M.a , Pietka, A.a , Salyer, P.a , Waters, E.A.c , Chen, L.-S.a , Bierut, L.J.a

a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Communication Design, Sam Fox School of Design & Visual Arts, Washington University, St. Louis, MO, United States
c Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Despite major advancements in genomic medicine, research to optimize the design and communication of genetically informed interventions in behavioral health has lagged. The goal of this study was to engage potential end users in participatory codesign of a personalized genetically informed risk tool to intervene on high-risk health behaviors. We used structured interviews to examine end-user attitudes and interest in personalized genetics, qualitative interviews to guide iterative design of a genetically informed tool, and questionnaires to assess acceptability and potential utility of the tool. Participants expressed strong demand for using personal genetics to inform smoking and alcohol-related disease risk and guide treatment (78%-95% agreed). Via iterative design feedback, we cocreated a genetically informed risk profile featuring (i) explanation of genetic and phenotypic markers used to construct a risk algorithm, (ii) personalized risks and benefits of healthy behavior change, and (iii) recommended actions with referral to freely available resources. Participants demonstrated sufficient understanding and cited motivating behavior change as the most useful purpose of the tool. In three phases, we confirmed strong desire for personalized genetics on high-risk health behaviors; codesigned a genetically informed profile with potential end users; and found high acceptability, comprehensibility, and perceived usefulness of the profile. As scientific discovery of genomic medicine advances in behavioral health, we must develop the tools to communicate these discoveries to consumers who stand to benefit. The potential of genomic medicine to engage populations and personalize behavioral health treatment depends, in part, on preparatory studies to design for the future implementation of genetically informed interventions. ©2020 American Association for Cancer Research.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Corrigendum: Peer Victimization and Dysfunctional Reward Processing: ERP and Behavioral Responses to Social and Monetary Rewards (Frontiers in Behavioral Neuroscience, (2019), 13, 10.3389/fnbeh.2019.00120)” (2020) Frontiers in Behavioral Neuroscience

Corrigendum: Peer Victimization and Dysfunctional Reward Processing: ERP and Behavioral Responses to Social and Monetary Rewards (Frontiers in Behavioral Neuroscience, (2019), 13, 10.3389/fnbeh.2019.00120)
(2020) Frontiers in Behavioral Neuroscience, 14, art. no. 100, . 

Rappaport, B.I.a , Hennefield, L.b , Kujawa, A.c , Arfer, K.B.d , Kelly, D.b , Kappenman, E.S.e , Luby, J.L.b , Barch, D.M.a b f

a Department of Psychological Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
b Department of Psychiatry, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
c Department of Psychology & Human Development, Vanderbilt University, Nashville, TN, United States
d Center for HIV Identification, Prevention, and Treatment Services, University of California, Los Angeles, Los Angeles, CA, United States
e Department of Psychology, San Diego State University, San Diego, CA, United States
f Department of Radiology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States

Abstract
In the original article, there was a mistake in Figure 2 as published. In the original article, we had stated that “all data were re-referenced to the average of Tp9 and Tp10” in the Data Analysis section of the Materials and Methods. Although this was our intention, we recently discovered that our scripts had in fact been re-referencing the data to the average of Tp9, Tp10, and Cz electrodes accidentally. Repeating the analyses using the correct referencing and same trials from the original paper yields identical results to those reported in the original article. The corrected Figure 2 appears below. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated. Copyright © 2020 Rappaport, Hennefield, Kujawa, Arfer, Kelly, Kappenman, Luby and Barch.

Author Keywords
adolescence;  depression;  event-related potentials (ERP);  monetary reward;  peer victimization;  reward;  social reward

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

“Overall survival prediction in glioblastoma patients using structural magnetic resonance imaging (MRI): Advanced radiomic features may compensate for lack of advanced MRI modalities” (2020) Journal of Medical Imaging

Overall survival prediction in glioblastoma patients using structural magnetic resonance imaging (MRI): Advanced radiomic features may compensate for lack of advanced MRI modalities
(2020) Journal of Medical Imaging, 7 (3), art. no. 031505, . 

Bakas, S.a , Bakas, S.b , Bakas, S.c , Shukla, G.a , Shukla, G.d , Akbari, H.a , Akbari, H.b , Erus, G.a , Erus, G.b , Sotiras, A.a , Sotiras, A.b , Sotiras, A.e , Sotiras, A.f , Rathore, S.a , Rathore, S.b , Sako, C.a , Sako, C.b , Min Ha, S.a , Min Ha, S.b , Rozycki, M.a , Rozycki, M.b , Shinohara, R.T.a , Shinohara, R.T.g , Bilello, M.a , Bilello, M.b , Davatzikos, C.a , Davatzikos, C.b

a University of Pennsylvania, Perelman School of Medicine, Center for Biomedical Image Computing and Analytics, Richards Medical Research Laboratories, Philadelphia, PA, United States
b University of Pennsylvania, Perelman School of Medicine, Richards Medical Research Laboratories, Department of Radiology, Philadelphia, PA, United States
c University of Pennsylvania, Perelman School of Medicine, Richards Medical Research Laboratories, Department of Pathology and Laboratory Medicine, Philadelphia, PA, United States
d Thomas Jefferson University, Sidney Kimmel Cancer Center, Department of Radiation Oncology, Philadelphia, PA, United States
e Washington University in St. Louis, School of Medicine, Institute for Informatics, Saint Louis, MO, United States
f Washington University in St. Louis, Department of Radiology, Saint Louis, MO, United States
g University of Pennsylvania, Perelman School of Medicine, Penn Statistics in Imaging and Visualization Center, Department of Biostatistics, Epidemiology, and Informatics, Philadelphia, PA, United States

Abstract
Purpose: Glioblastoma, the most common and aggressive adult brain tumor, is considered noncurative at diagnosis, with 14 to 16 months median survival following treatment. There is increasing evidence that noninvasive integrative analysis of radiomic features can predict overall and progression-free survival, using advanced multiparametric magnetic resonance imaging (AdvmpMRI). If successfully applicable, such noninvasive markers can considerably influence patient management. However, most patients prior to initiation of therapy typically undergo only basic structural mpMRI (Bas-mpMRI, i.e., T1, T1-Gd, T2, and T2-fluid-attenuated inversion recovery) preoperatively, rather than Adv-mpMRI that provides additional vascularization (dynamic susceptibility contrast-MRI) and cell-density (diffusion tensor imaging) related information. Approach: We assess a retrospective cohort of 101 glioblastoma patients with available AdvmpMRI from a previous study, which has shown that an initial feature panel (IFP, i.e., intensity, volume, location, and growth model parameters) extracted from Adv-mpMRI can yield accurate overall survival stratification.We focus on demonstrating that equally accurate prediction models can be constructed using augmented radiomic feature panels (ARFPs, i.e., integrating morphology and textural descriptors) extracted solely from widely available Bas-mpMRI, obviating the need for using Adv-mpMRI.We extracted 1612 radiomic features from distinct tumor subregions to build multivariate models that stratified patients as long-, intermediate-, or short-survivors. Results: The classification accuracy of the model utilizing Adv-mpMRI protocols and the IFP was 72.77% and degraded to 60.89% when using only Bas-mpMRI. However, utilizing the ARFP on Bas-mpMRI improved the accuracy to 74.26%. Furthermore, Kaplan–Meier analysis demonstrated superior classification of subjects into short-, intermediate-, and long-survivor classes when using ARFP extracted from Bas-mpMRI. Conclusions: This quantitative evaluation indicates that accurate survival prediction in glioblastoma patients is feasible using solely Bas-mpMRI and integrative advanced radiomic features, which can compensate for the lack of Adv-mpMRI. Our finding holds promise for generalization across multiple institutions that may not have access to Adv-mpMRI and to better inform clinical decision-making about aggressive interventions and clinical trials. © 2020 SPIE. All rights reserved.

Author Keywords
glioblastoma;  multivariate;  prediction;  prognosis;  radiomics;  survival

Document Type: Article
Publication Stage: Final
Source: Scopus

“Quality of life and caregiver burden in familial frontotemporal lobar degeneration: Analyses of symptomatic and asymptomatic individuals within the LEFFTDS cohort” (2020) Alzheimer’s and Dementia

Quality of life and caregiver burden in familial frontotemporal lobar degeneration: Analyses of symptomatic and asymptomatic individuals within the LEFFTDS cohort
(2020) Alzheimer’s and Dementia, . 

Gentry, M.T.q , Lapid, M.I.q , Syrjanen, J.q , Calvert, K.q , Hughes, S.q , Brushaber, D.q , Kremers, W.q , Bove, J.a , Brannelly, P.b , Coppola, G.c , Dheel, C.q , Dickerson, B.d , Dickinson, S.e , Faber, K.f , Fields, J.q , Fong, J.g , Foroud, T.f , Forsberg, L.q , Gavrilova, R.q , Gearhart, D.q , Ghoshal, N.h , Goldman, J.i , Graff-Radford, J.q , Graff-Radford, N.j , Grossman, M.a , Haley, D.j , Heuer, H.g , Hsiung, G.-Y.k , Huey, E.i , Irwin, D.a , Jones, D.q , Jones, L.h , Kantarci, K.q , Karydas, A.g , Knopman, D.q , Kornak, J.g , Kramer, J.g , Kukull, W.l , Lucente, D.d , Lungu, C.m , Mackenzie, I.k , Manoochehri, M.i , McGinnis, S.d , Miller, B.g , Pearlman, R.n , Petrucelli, L.j , Potter, M.f , Rademakers, R.j , Ramos, E.M.c , Rankin, K.g , Rascovsky, K.a , Sengdy, P.k , Shaw, L.a , Tatton, N.e , Taylor, J.g , Toga, A.o , Trojanowski, J.a , Weintraub, S.p , Wong, B.d , Wszolek, Z.j , Boeve, B.F.q , Boxer, A.g , Rosen, H.g , the LEFFTDS Consortiumq

a University of Pennsylvania, Philadelphia, PA, United States
b Tau Consortium, Rainwater Charitable Foundation, Fort Worth, TX, United States
c UCLA, Los Angeles, CA, United States
d Harvard University/MGH, Boston, MA, United States
e Association for Frontotemporal Degeneration, Radnor, PA, United States
f National Cell Repository for Alzheimer’s Disease (NCRAD), Indiana University, Indianapolis, IN, United States
g UCSF, San Francisco, CA, United States
h Washington University, St. Louis, MO, United States
i Columbia University, New York, NY, United States
j Mayo Clinic, Jacksonville, FL, United States
k University of British Columbia, Vancouver, BC, Canada
l National Alzheimer’s Coordinating Center (NACC), University of Washington, Seattle, WA, United States
m National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, MD, United States
n Bluefield Project, San Francisco, CA, United States
o Laboratory of Neuroimaging (LONI), USC, Los Angeles, CA, United States
p Northwestern University, Chicago, IL, United States
q Mayo Clinic, Rochester, MN, United States

Abstract
Objective: The Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects evaluates familial frontotemporal lobar degeneration (FTLD) kindreds with MAPT, GRN, or C9orf72 mutations. Objectives were to examine whether health-related quality of life (HRQoL) correlates with clinical symptoms and caregiver burden, and whether self-rated and informant-rated HRQoL would correlate with each other. Methods: Individuals were classified using the Clinical Dementia Rating (CDR®) Scale plus National Alzheimer’s Coordinating Center (NACC) FTLD. HRQoL was measured with DEMQOL and DEMQOL-proxy; caregiver burden with the Zarit Burden Interview (ZBI). For analysis, Pearson correlations and weighted kappa statistics were calculated. Results: The cohort of 312 individuals included symptomatic and asymptomatic individuals. CDR® plus NACC FTLD was negatively correlated with DEMQOL (r = −0.20, P =.001), as were ZBI and DEMQOL (r = −0.22, P =.0009). There was fair agreement between subject and informant DEMQOL (κ = 0.36, P <.0001). Conclusion: Lower HRQoL was associated with higher cognitive/behavior impairment and higher caregiver burden. These findings demonstrate the negative impact of FTLD on individuals and caregivers. © 2020 the Alzheimer’s Association

Author Keywords
C9orf72;  frontotemporal dementia;  GRN;  MAPT;  quality of life;  tau;  TDP-43

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

“Local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia” (2020) EMBO Journal

Local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia
(2020) EMBO Journal, . 

Scott-Hewitt, N.a b , Perrucci, F.c d , Morini, R.c , Erreni, M.e , Mahoney, M.a , Witkowska, A.f g , Carey, A.a , Faggiani, E.c , Schuetz, L.T.d , Mason, S.a , Tamborini, M.c , Bizzotto, M.d , Passoni, L.c , Filipello, F.c d k , Jahn, R.f h , Stevens, B.a b i , Matteoli, M.c j

a F.M. Kirby Center for Neurobiology, Boston Children’s Hospital, Boston, MA, United States
b Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, United States
c Laboratory of Pharmacology and Brain Pathology, Neurocenter, Humanitas Clinical and Research Center – IRCCS, Rozzano (MI), Italy
d Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy
e Unit of Advanced Optical Microscopy, Humanitas Clinical and Research Center – IRCCS, Rozzano (MI), Italy
f Laboratory of Neurobiology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
g Department of Molecular Pharmacology and Cell Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany
h University of Göttingen, Göttingen, Germany
i Howard Hughes Medical Institute, Boston Children’s Hospital, Boston, MA, United States
j CNR Institute of Neuroscience, Milano, Italy
k Department of Neurology, Washington University, St. Louis, MO, United States

Abstract
Neuronal circuit assembly requires the fine balance between synapse formation and elimination. Microglia, through the elimination of supernumerary synapses, have an established role in this process. While the microglial receptor TREM2 and the soluble complement proteins C1q and C3 are recognized as key players, the neuronal molecular components that specify synapses to be eliminated are still undefined. Here, we show that exposed phosphatidylserine (PS) represents a neuronal “eat-me” signal involved in microglial-mediated pruning. In hippocampal neuron and microglia co-cultures, synapse elimination can be partially prevented by blocking accessibility of exposed PS using Annexin V or through microglial loss of TREM2. In vivo, PS exposure at both hippocampal and retinogeniculate synapses and engulfment of PS-labeled material by microglia occurs during established developmental periods of microglial-mediated synapse elimination. Mice deficient in C1q, which fail to properly refine retinogeniculate connections, have elevated presynaptic PS exposure and reduced PS engulfment by microglia. These data provide mechanistic insight into microglial-mediated synapse pruning and identify a novel role of developmentally regulated neuronal PS exposure that is common among developing brain structures. © 2020 The Authors. Published under the terms of the CC BY NC ND 4.0 license

Author Keywords
C1q;  microglia;  phosphatidylserine;  synapse pruning;  TREM2

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

“Real-world experience with direct brain-responsive neurostimulation for focal onset seizures” (2020) Epilepsia

Real-world experience with direct brain-responsive neurostimulation for focal onset seizures
(2020) Epilepsia, . 

Razavi, B.a , Rao, V.R.b , Lin, C.a , Bujarski, K.A.c , Patra, S.E.d , Burdette, D.E.d , Geller, E.B.e , Brown, M.-G.M.f , Johnson, E.A.g , Drees, C.f , Chang, E.F.b , Greenwood, J.E.h , Heck, C.N.h , Jobst, B.C.c , Gwinn, R.P.i , Warner, N.M.i , Halpern, C.H.a

a Stanford University School of Medicine, Stanford, CA, United States
b University of California, San Francisco, CA, United States
c Dartmouth Hitchcock Medical Center, Lebanon, NH, United States
d Spectrum Health Center, Michigan State University School of Human Medicine, East Lansing, MI, United States
e St. Barnabas Medical Center, Livingston, NJ, United States
f University of Colorado, Denver, CO, United States
g Washington University School of Medicine, St. Louis, MO, United States
h Keck School of Medicine at University of Southern California, Los Angeles, CA, United States
i Swedish Neuroscience Institute, Seattle, WA, United States

Abstract
Objective: The RNS System is a direct brain-responsive neurostimulation system that is US Food and Drug Administration–approved for adults with medically intractable focal onset seizures based on safety and effectiveness data from controlled clinical trials. The purpose of this study was to retrospectively evaluate the real-world safety and effectiveness of the RNS System. Methods: Eight comprehensive epilepsy centers conducted a chart review of patients treated with the RNS System for at least 1 year, in accordance with the indication for use. Data included device-related serious adverse events and the median percent change in disabling seizure frequency from baseline at years 1, 2, and 3 of treatment and at the most recent follow-up. Results: One hundred fifty patients met the criteria for analysis. The median reduction in seizures was 67% (interquartile range [IQR] = 33%-93%, n = 149) at 1 year, 75% (IQR = 50%-94%, n = 93) at 2 years, 82% (IQR = 50%-96%, n = 38) at ≥3 years, and 74% (IQR = 50%-96%, n = 150) at last follow-up (mean = 2.3 years). Thirty-five percent of patients had a ≥90% seizure frequency reduction, and 18% of patients reported being clinically seizure-free at last follow-up. Seizure frequency reductions were similar regardless of patient age, age at epilepsy onset, duration of epilepsy, seizure onset in mesial temporal or neocortical foci, magnetic resonance imaging findings, prior intracranial monitoring, prior epilepsy surgery, or prior vagus nerve stimulation treatment. The infection rate per procedure was 2.9% (6/150 patients); five of the six patients had an implant site infection, and one had osteomyelitis. Lead revisions were required in 2.7% (4/150), and 2.0% (3/150) of patients had a subdural hemorrhage, none of which had long-lasting neurological consequences. Significance: In this real-world experience, safety was similar and clinical seizure outcomes exceeded those of the prospective clinical trials, corroborating effectiveness of this therapy and suggesting that clinical experience has informed more effective programming. © 2020 International League Against Epilepsy

Author Keywords
brain-responsive neurostimulation;  drug-resistant;  medically intractable epilepsy;  RNS System

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

“Global motion detection and censoring in high-density diffuse optical tomography” (2020) Human Brain Mapping

Global motion detection and censoring in high-density diffuse optical tomography
(2020) Human Brain Mapping, . 

Sherafati, A.a , Snyder, A.Z.b c , Eggebrecht, A.T.b d e , Bergonzi, K.M.f , Burns-Yocum, T.M.g , Lugar, H.M.h , Ferradal, S.L.i , Robichaux-Viehoever, A.c , Smyser, C.D.b c j , Palanca, B.J.k , Hershey, T.b g , Culver, J.P.a b d e

a Department of Physics, Washington University in St. Louis, St. Louis, MO, United States
b Department of Radiology, Washington University School of Medicine in St, St. Louis, MO, United States
c Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
d Department of Biomedical Engineering, Washington University School in St. Louis, St. Louis, MO, United States
e Division of Biology and Biomedical Sciences, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
f L3Harris, 400 Initiative Dr, Rochester, NY 14624, United States
g Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, United States
h Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
i Department Of Intelligent Systems Engineering, Indiana University, Bloomington, IN, United States
j Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, United States
k Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. LouisMO, United States

Abstract
Motion-induced artifacts can significantly corrupt optical neuroimaging, as in most neuroimaging modalities. For high-density diffuse optical tomography (HD-DOT) with hundreds to thousands of source-detector pair measurements, motion detection methods are underdeveloped relative to both functional magnetic resonance imaging (fMRI) and standard functional near-infrared spectroscopy (fNIRS). This limitation restricts the application of HD-DOT in many challenging imaging situations and subject populations (e.g., bedside monitoring and children). Here, we evaluated a new motion detection method for multi-channel optical imaging systems that leverages spatial patterns across measurement channels. Specifically, we introduced a global variance of temporal derivatives (GVTD) metric as a motion detection index. We showed that GVTD strongly correlates with external measures of motion and has high sensitivity and specificity to instructed motion—with an area under the receiver operator characteristic curve of 0.88, calculated based on five different types of instructed motion. Additionally, we showed that applying GVTD-based motion censoring on both hearing words task and resting state HD-DOT data with natural head motion results in an improved spatial similarity to fMRI mapping. We then compared the GVTD similarity scores with several commonly used motion correction methods described in the fNIRS literature, including correlation-based signal improvement (CBSI), temporal derivative distribution repair (TDDR), wavelet filtering, and targeted principal component analysis (tPCA). We find that GVTD motion censoring on HD-DOT data outperforms other methods and results in spatial maps more similar to those of matched fMRI data. © 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.

Author Keywords
functional near-infrared spectroscopy;  high-density diffuse optical tomography;  motion artifact;  motion censoring;  optical neuroimaging

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

“Analysis of FGF20-regulated genes in organ of Corti progenitors by translating ribosome affinity purification” (2020) Developmental Dynamics

Analysis of FGF20-regulated genes in organ of Corti progenitors by translating ribosome affinity purification
(2020) Developmental Dynamics, . 

Yang, L.M.a , Stout, L.b , Rauchman, M.b , Ornitz, D.M.a

a Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
b Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: Understanding the mechanisms that regulate hair cell (HC) differentiation in the organ of Corti (OC) is essential to designing genetic therapies for hearing loss due to HC loss or damage. We have previously identified Fibroblast Growth Factor 20 (FGF20) as having a key role in HC and supporting cell differentiation in the mouse OC. To investigate the genetic landscape regulated by FGF20 signaling in OC progenitors, we employ Translating Ribosome Affinity Purification combined with Next Generation RNA Sequencing (TRAPseq) in the Fgf20 lineage. Results: We show that TRAPseq targeting OC progenitors effectively enriched for RNA from this rare cell population. TRAPseq identified differentially expressed genes (DEGs) downstream of FGF20, including Etv4, Etv5, Etv1, Dusp6, Hey1, Hey2, Heyl, Tectb, Fat3, Cpxm2, Sall1, Sall3, and cell cycle regulators such as Cdc20. Analysis of Cdc20 conditional-null mice identified decreased cochlea length, while analysis of Sall1-null and Sall1-ΔZn2-10 mice, which harbor a mutation that causes Townes-Brocks syndrome, identified a decrease in outer hair cell number. Conclusions: We present two datasets: genes with enriched expression in OC progenitors, and DEGs downstream of FGF20 in the embryonic day 14.5 cochlea. We validate select DEGs via in situ hybridization and in vivo functional studies in mice. © 2020 Wiley Periodicals LLC

Author Keywords
cochlea;  hair cell;  hearing loss;  RNAseq;  SALL1;  Townes-Brocks syndrome

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

“Impact of circadian and diurnal rhythms on cellular metabolic function and neurodegenerative diseases” (2020) International Review of Neurobiology

Impact of circadian and diurnal rhythms on cellular metabolic function and neurodegenerative diseases
(2020) International Review of Neurobiology, . 

Smith, S.K.a , Musiek, E.S.b

a Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
The 24-h rotational period of the earth has driven evolution of biological systems that serve to synchronize organismal physiology and behavior to this predictable environmental event. In mammals, the circadian (circa, “about” and dia, “a day”) clock keeps 24-h time at the organismal and cellular level, optimizing biological function for a given time of day. The most obvious circadian output is the sleep-wake cycle, though countless bodily functions, ranging from hormone levels to cognitive function, are influenced by the circadian clock. Here we discuss the regulation of metabolic pathways by the circadian clock, discuss the evidence implicating circadian and sleep disruption in neurodegenerative diseases, and suggest some possible connections between the clock, metabolism, and neurodegenerative disease. © 2020 Elsevier Inc.

Author Keywords
Sirtuins;  Alzheimer’s disease (AD);  Circadian rhythms;  Clocks;  Huntington’s disease (HD);  Metabolism;  Mitochondria;  NAD+;  Neurodegeneration;  Parkinson’s disease (PD);  Sleep disorders;  Suprachiasmatic nucleus (SCN)

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

“Genome-wide admixture mapping of DSM-IV alcohol dependence, criterion count, and the self-rating of the effects of ethanol in African American populations” (2020) American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics

Genome-wide admixture mapping of DSM-IV alcohol dependence, criterion count, and the self-rating of the effects of ethanol in African American populations
(2020) American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, . 

Lai, D.a , Kapoor, M.b , Wetherill, L.a , Schwandt, M.c , Ramchandani, V.A.d , Goldman, D.c , Chao, M.b , Almasy, L.e , Bucholz, K.f , Hart, R.P.g , Kamarajan, C.h , Meyers, J.L.h , Nurnberger, J.I.a i , Tischfield, J.j , Edenberg, H.J.a k , Schuckit, M.l , Goate, A.b , Scott, D.M.m , Porjesz, B.h , Agrawal, A.f , Foroud, T.a

a Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
b Department of Neuroscience, Icahn School of Medicine at Mt. Sinai, New York, NY, United States
c Office of the Clinical Director, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, United States
d Section on Human Psychopharmacology, Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, United States
e Department of Biomedical and Health Informatics, Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA, United States
f Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
g Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States
h Henri Begleiter Neurodynamics Lab, Department of Psychiatry, State University of New York, Downstate Medical Center, Brooklyn, NY, United States
i Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, United States
j Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ, United States
k Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States
l Department of Psychiatry, University of California, San Diego Medical School, San Diego, CA, United States
m Departments of Pediatrics and Human Genetics, Howard University, Washington, District of Columbia, United States

Abstract
African Americans (AA) have lower prevalence of alcohol dependence and higher subjective response to alcohol than European Americans. Genome-wide association studies (GWAS) have identified genes/variants associated with alcohol dependence specifically in AA; however, the sample sizes are still not large enough to detect variants with small effects. Admixture mapping is an alternative way to identify alcohol dependence genes/variants that may be unique to AA. In this study, we performed the first admixture mapping of DSM-IV alcohol dependence diagnosis, DSM-IV alcohol dependence criterion count, and two scores from the self-rating of effects of ethanol (SRE) as measures of response to alcohol: the first five times of using alcohol (SRE-5) and average of SRE across three times (SRE-T). Findings revealed a region on chromosome 4 that was genome-wide significant for SRE-5 (p value = 4.18E-05). Fine mapping did not identify a single causal variant to be associated with SRE-5; instead, conditional analysis concluded that multiple variants collectively explained the admixture mapping signal. PPARGC1A, a gene that has been linked to alcohol consumption in previous studies, is located in this region. Our finding suggests that admixture mapping is a useful tool to identify genes/variants that may have been missed by current GWAS approaches in admixed populations. © 2020 Wiley Periodicals LLC

Author Keywords
admixture mapping;  African American;  criterion count;  DSM-IV alcohol dependence;  response to ethanol

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

“A Gain-of-Function Mutation in KCNMA1 Causes Dystonia Spells Controlled With Stimulant Therapy” (2020) Movement Disorders

A Gain-of-Function Mutation in KCNMA1 Causes Dystonia Spells Controlled With Stimulant Therapy
(2020) Movement Disorders, . 

Zhang, G.a , Gibson, R.A.b , McDonald, M.b , Liang, P.c , Kang, P.W.a , Shi, J.a , Yang, H.c d , Cui, J.a , Mikati, M.A.b d

a Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
b Department of Pediatrics, Duke University Medical Center, Durham, NC, United States
c Department of Biochemistry, Duke University Medical Center, Durham, NC, United States
d Department of Neurobiology, Duke University Medical Center, Durham, NC, United States

Abstract
Background: The mutations of KCNMA1 BK-type K+ channel have been identified in patients with various movement disorders. The underlying pathophysiology and corresponding therapeutics are lacking. Objectives: To report our clinical and biophysical characterizations of a novel de novo KCNMA1 variant, as well as an effective therapy for the patient’s dystonia-atonia spells. Methods: Combination of phenotypic characterization, therapy, and biophysical characterization of the patient and her mutation. Results: The patient had >100 dystonia-atonia spells per day with mild cerebellar atrophy. She also had autism spectrum disorder, intellectual disability, and attention deficit hyperactivity disorder. Whole-exome sequencing identified a heterozygous de novo BK N536H mutation. Our biophysical characterization demonstrates that N536H is a gain-of-function mutation with markedly enhanced voltage-dependent activation. Remarkably, administration of dextroamphetamine completely suppressed the dystonia-atonia spells. Conclusions: BK N536H is a gain-of-function that causes dystonia and other neurological symptoms. Our stimulant therapy opens a new avenue to mitigate KCNMA1-linked movement disorders. © 2020 International Parkinson and Movement Disorder Society. © 2020 International Parkinson and Movement Disorder Society

Author Keywords
BK channelopathy;  dystonia;  KCNMA1;  movement disorders;  stimulants

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

“Management of Nerve Trauma in the Mangled Extremity” (2020) Current Trauma Reports

Management of Nerve Trauma in the Mangled Extremity
(2020) Current Trauma Reports, . 

Hu, J.a , Bruce, J.G.a , Moore, A.M.b

a Washington University in Saint Louis School of Medicine, St. Louis, MO, United States
b The Ohio State University Wexner Medical Center, Columbus, OH, United States

Abstract
Purpose of Review: In this review, we present a principled approach to surgical management of nerve injuries in the mangled extremity. We discuss initial evaluation of the mangled extremity, key considerations with respect to surgical planning and timing, and current options for restoration of function including nerve repair, interposition grafts, nerve transfers, and other adjunctive techniques. Recent Findings: Significant advances have been made in nerve transfer techniques, providing another option for restoration of function in extremity nerve injury. Summary: Management of nerve injuries in the mangled extremity is a challenging endeavor that requires significant planning and consideration by the nerve surgeon. Optimal recovery of function necessitates careful selection of the most appropriate surgical option for a given patient. © 2020, Springer Nature Switzerland AG.

Author Keywords
Mangled extremity;  Nerve injury;  Nerve transfer;  Nerve trauma

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

“Starting or Switching to an Integrase Inhibitor-Based Regimen Affects PTSD Symptoms in Women with HIV” (2020) AIDS and Behavior

Starting or Switching to an Integrase Inhibitor-Based Regimen Affects PTSD Symptoms in Women with HIV
(2020) AIDS and Behavior, . 

Kamkwalala, A.R.a , Wang, K.b , O’Halloran, J.c , Williams, D.W.d e , Dastgheyb, R.a , Fitzgerald, K.C.a , Spence, A.B.f , Maki, P.M.g , Gustafson, D.R.h , Milam, J.i , Sharma, A.j , Weber, K.M.k , Adimora, A.A.l , Ofotokun, I.m , Sheth, A.N.m , Lahiri, C.D.m , Fischl, M.A.n , Konkle-Parker, D.o , Xu, Y.c p , Rubin, L.H.a q r

a Department of Neurology, Johns Hopkins University School of Medicine, 600 N. Wolfe Street/ Meyer 6-113, Baltimore, MD 21287-7613, United States
b Department of Applied Mathematics and Statistics, Johns Hopkins University, Baltimore, MD, United States
c Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
d Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
e Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
f Department of Medicine, Division of Infectious Disease and Travel Medicine, Georgetown University, Washington, DC, United States
g Departments of Psychiatry, Psychology and OB/GYN, University of Illinois at Chicago, Chicago, IL, United States
h Department of Neurology, State University of New York Downstate Health Sciences University, Brooklyn, NY, United States
i Institute for Health Promotion & Disease Prevention Research, University of Southern California, Los Angeles, CA, United States
j Albert Einstein College of Medicine, Bronx, NY, United States
k CORE Center, Cook County Health and Hektoen Institute of Medicine, Chicago, IL, United States
l Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
m Department of Medicine, Division of Infectious Diseases, Emory University, Atlanta, GA, United States
n University of Miami Miller School of Medicine, Miami, FL, United States
o Division of Infectious Diseases, University of Mississippi Medical Center, Jackson, MS, United States
p Division of Biostatistics and Bioinformatics at The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
q Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, United States
r Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Abstract
As the use of Integrase inhibitor (INSTI)-class antiretroviral medications becomes more common to maintain long-term viral suppression, early reports suggest the potential for CNS side-effects when starting or switching to an INSTI-based regimen. In a population already at higher risk for developing mood and anxiety disorders, these drugs may have significant effects on PTSD scale symptom scores, particularly in women with HIV (WWH). A total of 551 participants were included after completing ≥ 1 WIHS study visits before and after starting/switching to an INSTI-based ART regimen. Of these, 14% were ART naïve, the remainder switched from primarily a protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen. Using multivariable linear mixed effects models, we compared PTSD Civilian Checklist subscale scores before and after a “start/switch” to dolutegravir (DTG), raltegravir (RAL), or elvitegravir (EVG). Start/switch to EVG improved re-experiencing subscale symptoms (P’s < 0.05). Switching to EVG improved symptoms of avoidance (P = 0.01). Starting RAL improved arousal subscale symptoms (P = 0.03); however, switching to RAL worsened re-experiencing subscale symptoms (P < 0.005). Starting DTG worsened avoidance subscale symptoms (P = 0.03), whereas switching to DTG did not change subscale or overall PTSD symptoms (P’s > 0.08). In WWH, an EVG-based ART regimen is associated with improved PTSD symptoms, in both treatment naïve patients and those switching from other ART. While a RAL-based regimen was associated with better PTSD symptoms than in treatment naïve patients, switching onto a RAL-based regimen was associated with worse PTSD symptoms. DTG-based regimens either did not affect, or worsened symptoms, in both naïve and switch patients. Further studies are needed to determine mechanisms underlying differential effects of EVG, RAL and DTG on stress symptoms in WWH. © 2020, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Antiretroviral;  HIV1;  Integrase inhibitors;  PTSD;  Stress;  Women

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

“Neuroinflammatory Disease as an Isolated Manifestation of Hemophagocytic Lymphohistiocytosis” (2020) Journal of Clinical Immunology

Neuroinflammatory Disease as an Isolated Manifestation of Hemophagocytic Lymphohistiocytosis
(2020) Journal of Clinical Immunology, . 

Blincoe, A.a b , Heeg, M.c d e , Campbell, P.K.f , Hines, M.g , Khojah, A.h , Klein-Gitelman, M.h i , Talano, J.-A.j , Speckmann, C.c k , Touzot, F.a , Lankester, A.l , Legger, G.E.m , Rivière, J.G.n o , Garcia-Prat, M.n o , Alonso, L.p , Putti, M.C.q , Lehmberg, K.r , Maier, S.r , El Chazli, Y.s , Elmaksoud, M.A.t , Astigarraga, I.u , Kurjane, N.v w , Bulina, I.v x , Kenina, V.w y , Bryceson, Y.z , Rascon, J.aa ab , Lortie, A.ac , Goldstein, G.ad , Booth, C.ae , Worth, A.ae , Wassmer, E.af , Schmitt, E.G.ag , Warren, J.T.ag , Bednarski, J.J.ag , Ali, S.ah , Chiang, K.-Y.ah ai , Krueger, J.ah ai , Henry, M.M.aj , Holland, S.M.ak , Marsh, R.A.al , Ehl, S.c , Haddad, E.a

a CHU Sainte-Justine, Department of Pediatrics, Department of Microbiology, Infectious Diseases and Immunology, University of Montreal, Montreal, QC H3T 1C5, Canada
b Department of Paediatric Immunology and Allergy, Starship Children’s Health, Auckland, New Zealand
c Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Breisacher Strasse 115, Freiburg, 79106, Germany
d Center for Pediatrics, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
e Berta-Ottenstein-Programme, Faculty of Medicine, University of Freiburg, Freiburg, Germany
f Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, United States
g Department of Pediatric Medicine, Division of Critical Care, St Jude Children’s Research Hospital, Memphis, TN, United States
h Department of Rheumatology, Ann and Robert H Lurie Children’s Hospital and Children’s Hospital of Chicago, Chicago, IL, United States
i Department of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
j Pediatric Hematology and Oncology, Children’s Hospital of Wisconsin-Milwaukee Campus, Milwaukee, WI, United States
k Department of Pediatric and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
l Willem-Alexander Children’s Hospital, Department of Pediatrics, Leiden University Medical Center, Leiden, Netherlands
m Department of Pediatrics, University of Groningen, University Medical Centre Groningen, Groningen, Netherlands
n Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d’Hebron, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
o Jeffrey Modell Foundation Excellence Centre, Barcelona, Spain
p Pediatric Hematology and Oncology Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
q Department of Pediatrics, University of Padua Medical School, Padua, Italy
r Division of Pediatric Stem Cell Transplantation and Immunology, University Medical Center, Hamburg, Germany
s Hematology and Oncology Unit, Alexandria University Children’s Hospital, Department of Pediatrics, Faculty of Medicine, Alexandria University, Alexandria, Egypt
t Neurology Unit, Alexandria University Children’s Hospital, Department of Pediatrics, Faculty of Medicine, Alexandria University, Alexandria, Egypt
u Department of Pediatrics, Hospital Universitario Cruces, IIS BioCruces Bizkaia, Department of Pediatrics, Faculty of Medicine, UPV/EHU, Barakaldo, Bizkaia, Spain
v Stradins Clinical University Hospital, Riga, Latvia
w Department of Biology and Microbiology, Rigas Stradins University, Riga, Latvia
x Department of Rheumatology, Stradins Clinical University Hospital, Riga, Latvia
y Department of Neurology, Hospital Gailezers, Riga, Latvia
z Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
aa Center for Pediatric Oncology and Hematology, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania
ab Institute of Clinical Medicine, Vilnius University, Vilnius, Lithuania
ac CHU Sainte Justine, Department of Neurology, Cerebral Electrophysiology Laboratory, Department of Neurosciences, University of Montreal, Montreal, QC, Canada
ad Department of Pediatric Hematology-Oncology, Hadassah-Hebrew University Medical Center, Ein Kerem, Jerusalem, Israel
ae Department of Pediatric Immunology, Great Ormond Street Hospital, London, WC1N 3JH, United Kingdom
af Department of Neurology, Birmingham Women’s and Children’s Hospital, Birmingham, United Kingdom
ag Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
ah Division of Hematology/Oncology/BMT, The Hospital for Sick Children, Toronto, ON, Canada
ai Department of Pediatrics, University of Toronto, Toronto, ON, Canada
aj Centre for Cancer and Blood Disorders, Phoenix Children’s Hospital, Phoenix, United States
ak Division of Intramural Research, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States
al Department of Pediatrics, University of Cincinnati, Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Medical Centre, Cincinnati, OH, United States

Abstract
Isolated neuroinflammatory disease has been described in case reports of familial hemophagocytic lymphohistiocytosis (FHL), but the clinical spectrum of disease manifestations, response to therapy and prognosis remain poorly defined. We combined an international survey with a literature search to identify FHL patients with (i) initial presentation with isolated neurological symptoms; (ii) absence of cytopenia and splenomegaly at presentation; and (iii) systemic HLH features no earlier than 3 months after neurological presentation. Thirty-eight (20 unreported) patients were identified with initial diagnoses including acute demyelinating encephalopathy, leukoencephalopathy, CNS vasculitis, multiple sclerosis, and encephalitis. Median age at presentation was 6.5 years, most commonly with ataxia/gait disturbance (75%) and seizures (53%). Diffuse multifocal white matter changes (79%) and cerebellar involvement (61%) were common MRI findings. CSF cell count and protein were increased in 22/29 and 15/29 patients, respectively. Fourteen patients progressed to systemic inflammatory disease fulfilling HLH-2004 criteria at a mean of 36.9 months after initial neurological presentation. Mutations were detected in PRF1 in 23 patients (61%), RAB27A in 10 (26%), UNC13D in 3 (8%), LYST in 1 (3%), and STXBP2 in 1 (3%) with a mean interval to diagnosis of 28.3 months. Among 19 patients who underwent HSCT, 11 neurologically improved, 4 were stable, one relapsed, and 3 died. Among 14 non-transplanted patients, only 3 improved or had stable disease, one relapsed, and 10 died. Isolated CNS-HLH is a rare and often overlooked cause of inflammatory brain disease. HLH-directed therapy followed by HSCT seems to improve survival and outcome. © 2020, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
CNS disease;  CNS inflammation;  Familial hemophagocytic lymphohistiocytosis;  therapy

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

“Older molecular brain age in severe mental illness” (2020) Molecular Psychiatry

Older molecular brain age in severe mental illness
(2020) Molecular Psychiatry, . 

Lin, C.-W.a b , Chang, L.-C.a c , Ma, T.a d , Oh, H.e f , French, B.e , Puralewski, R.e , Mathews, F.e , Fang, Y.a , Lewis, D.A.e , Kennedy, J.L.f , Mueller, D.f , Marshe, V.S.f g , Jaffe, A.h , Chen, Q.h , Ursini, G.h , Weinberger, D.h , Newman, A.B.i , Lenze, E.J.j , Nikolova, Y.S.f , Tseng, G.C.a k , Sibille, E.e f g l

a Department of Biostatistics, Graduate school of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, United States
b Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI 53226, United States
c Department of Mathematical Sciences, Florida Atlantic University, Boca Raton, FL 33431, United States
d Department of Epidemiology and Biostatistics, University of Maryland, College Park, MD 20742, United States
e Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15312, United States
f Campbell Family Mental Health Research Institute of CAMH, Department of Psychiatry, University of Toronto, Toronto, ON M5T1R8, Canada
g Institute of Medical Science, University of Toronto, Toronto, ON, Canada
h Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, United States
i Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
j Department of Psychiatry, Washington University, St. Louis, MO 63130, United States
k Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA 15261, United States
l Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5T1R8, Canada

Abstract
Psychiatric disorders are associated with accelerated aging and enhanced risk for neurodegenerative disorders. Brain aging is associated with molecular, cellular, and structural changes that are robust on the group level, yet show substantial inter-individual variability. Here we assessed deviations in gene expression from normal age-dependent trajectories, and tested their validity as predictors of risk for major mental illnesses and neurodegenerative disorders. We performed large-scale gene expression and genotype analyses in postmortem samples of two frontal cortical brain regions from 214 control subjects aged 20–90 years. Individual estimates of “molecular age” were derived from age-dependent genes, identified by robust regression analysis. Deviation from chronological age was defined as “delta age”. Genetic variants associated with deviations from normal gene expression patterns were identified by expression quantitative trait loci (cis-eQTL) of age-dependent genes or genome-wide association study (GWAS) on delta age, combined into distinct polygenic risk scores (PRScis-eQTL and PRSGWAS), and tested for predicting brain disorders or pathology in independent postmortem expression datasets and clinical cohorts. In these validation datasets, molecular ages, defined by 68 and 76 age-related genes for two brain regions respectively, were positively correlated with chronological ages (r = 0.88/0.91), elevated in bipolar disorder (BP) and schizophrenia (SCZ), and unchanged in major depressive disorder (MDD). Exploratory analyses in independent clinical datasets show that PRSs were associated with SCZ and MDD diagnostics, and with cognition in SCZ and pathology in Alzheimer’s disease (AD). These results suggest that older molecular brain aging is a common feature of severe mental illnesses and neurodegeneration. © 2020, The Author(s), under exclusive licence to Springer Nature Limited.

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

“Brain Structure in Bilingual Compared to Monolingual Individuals with Alzheimer’s Disease: Proof of Concept” (2020) Journal of Alzheimer’s Disease: JAD

Brain Structure in Bilingual Compared to Monolingual Individuals with Alzheimer’s Disease: Proof of Concept
(2020) Journal of Alzheimer’s Disease: JAD, 76 (1), pp. 275-280. 

Raji, C.A.a , Meysami, S.b , Merrill, D.A.c d , Porter, V.R.b d , Mendez, M.F.b c e

a Mallinckrodt Institute of Radiology, Division of Neuroradiology, Washington University in St. Louis, St. Louis, MO, USA
b Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
c Department of Psychiatry & Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
d The John Wayne Cancer Institute and Pacific Neuroscience Institute, Providence and St. Johns Health Center, Santa Monica, CA, USA
e V.A. Greater Los Angeles Healthcare System, Los Angeles, CA, USA

Abstract
BACKGROUND: Bilingualism is increasingly recognized as protective in persons at risk for Alzheimer’s disease (AD). OBJECTIVE: Compare MRI measured brain volumes in matched bilinguals versus monolinguals with AD. METHODS: This IRB approved study analyzed T1 volumetric brain MRIs of patients with criteria-supported Probable AD. We identified 17 sequential bilinguals (any native language) with Probable AD, matched to 28 (62%) monolinguals on age and MMSE. Brain volumes were quantified with Neuroreader. Regional volumes as fraction of total intracranial volume (TIV) were compared between both groups, and Cohen’s D effect sizes were calculated for statistically significant structures. Partial correlations between bilingualism and brain volumes adjusted for age, gender, and TIV. RESULTS: Bilinguals had higher brain volumes in 37 structures. Statistical significance (p < 0.05) was observed in brainstem (t = 2.33, p = 0.02, Cohen’s D = 0.71) and ventral diencephalon (t = 3.01, p = 0.004, Cohen’s D = 0.91). Partial correlations showed statistical significance between bilingualism and larger volumes in brainstem (rp = 0 . 37, p = 0.01), thalamus (rp = 0.31, p = 0.04), ventral diencephalon (rp = 0.50, p = 0.001), and pallidum (rp = 0.38, p = 0.01). Bilingualism positively correlated with hippocampal volume, though not statistically significant (rp = 0.17, p = 0.26). No brain volumes were larger in monolinguals. CONCLUSION: Bilinguals demonstrated larger thalamic, ventral diencephalon, and brainstem volumes compared to matched monolinguals with AD. This may represent a neural substrate for increased cognitive reserve in bilingualism. Future studies should extrapolate this finding into cognitively normal persons at risk for AD.

Author Keywords
Alzheimer’s disease;  bilingual;  brain structure;  Neuroreader

Document Type: Article
Publication Stage: Final
Source: Scopus

“Mid- and Late-Life Leisure-Time Physical Activity and Global Brain Amyloid Burden: The Atherosclerosis Risk in Communities (ARIC)-PET Study” (2020) Journal of Alzheimer’s Disease: JAD

Mid- and Late-Life Leisure-Time Physical Activity and Global Brain Amyloid Burden: The Atherosclerosis Risk in Communities (ARIC)-PET Study
(2020) Journal of Alzheimer’s Disease: JAD, 76 (1), pp. 139-147. 

Palta, P.a , Heiss, G.b , Sharrett, A.R.c , Gabriel, K.P.d , Walker, K.e , Evenson, K.R.b , Knopman, D.f , Mosley, T.H.g , Wong, D.F.h i j , Gottesman, R.F.c e

a Division of General Medicine, Department of Medicine, Columbia University Irving Medical Center, NY, NY, United States
b Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, United States
c Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, MD, Baltimore, United States
d Department of Epidemiology, School of Public Health, The University of Alabama at Birmingham, Birmingham, AL, USA
e Department of Neurology, Johns Hopkins University School of Medicine, MD, Baltimore, United States
f Department of Neurology, Mayo Clinic, MN, Rochester, United States
g Department of Medicine, University of Mississippi Medical Center, MS, Jackson, United States
h Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, MD, Baltimore, United States
i Department of Environmental Health and Engineering, Johns Hopkins University Bloomberg School of Public Health, MD, Baltimore, United States
j Washington University in St. Louis, School of Medicine, Mallinckrodt Institute of Radiology, St. Louis, MO, USA

Abstract
BACKGROUND: Physical activity (PA) may slow the development of dementia by reducing the accumulation of amyloid. OBJECTIVE: We tested the hypothesis that higher levels of leisure-time PA in mid- or late-life were associated with lower brain amyloid burden in late-life among 326 non-demented participants from the Atherosclerosis Risk in Communities Study of brain florbetapir positron emission tomography (ARIC-PET) ancillary. METHODS: Self-reported PA was quantified using a past-year recall, interviewer-administered questionnaire in mid-life (1987-1989, aged 45-64 years) and late-life (2011-2013, aged 67-89 years). Continuous PA estimates were classified as 1) any leisure-time PA participation (yes/no); 2) meeting the 2018 United States’ PA guidelines (yes/no); and 3) per 1 standard deviation (SD) higher metabolic equivalent of task (MET) minutes per week (MET·min·wk-1). A brain magnetic resonance imaging scan with Florbetapir PET was performed in late-life. Adjusted odds ratios (OR) of elevated amyloid burden, defined as a global cortical standardized uptake value ratio (>1.2), compared to no elevated amyloid burden were estimated according to PA measures. RESULTS: Among the 326 participants (mean age: 76 years, 42% male, 41% Black), 52% had elevated brain amyloid burden. Mid-life leisure-time PA did not show a statistically significant lower odds of elevated late-life amyloid burden (OR = 0.71, 95% CI: 0.43-1.18). A 1 SD (970 MET. min. wk-1) higher PA level in mid-life was also not significantly associated withelevated amyloid burden (OR = 0.89, 95% CI: 0.69-1.15). Similar estimates were observed for meeting versus not meeting PA guidelines in both mid- and late-life. CONCLUSION: Self-reported higher mid- and late-life leisure-time PA were not significantly associated with lower amyloid burden. Data show a trend of an association, which is, however, imprecise, suggesting replication in larger studies.

Author Keywords
Amyloid;  cohort study;  epidemiology;  imaging;  PET;  physical activity

Document Type: Article
Publication Stage: Final
Source: Scopus

“Maximizing Safety in the Conduct of Alzheimer’s Disease Fluid Biomarker Research in the Era of COVID-19” (2020) Journal of Alzheimer’s Disease: JAD

Maximizing Safety in the Conduct of Alzheimer’s Disease Fluid Biomarker Research in the Era of COVID-19
(2020) Journal of Alzheimer’s Disease: JAD, 76 (1), pp. 27-31. 

Schindler, S.E.a b , Jicha, G.A.c d , Nelson, P.T.d e , Keene, C.D.f , Blennow, K.g h , Molinuevo, J.L.i j , Masters, C.L.k , Hansson, O.l , Teunissen, C.E.m , Galasko, D.n , Shaw, L.M.o , Levey, A.I.p , Silverberg, N.q

a Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
b Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
c Department of Neurology, University of Kentucky, KY, Lexington, United States
d Sanders-Brown Center on Aging, University of Kentucky, KY, Lexington, United States
e Department of Pathology, University of Kentucky, KY, Lexington, United States
f Department of Pathology, University of Washington, Seattle, WA, USA
g Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University Gothenburg, Mölndal, Sweden
h Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
i Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain
j Alzheimer’s Disease and Other Cognitive Disorders Unit, Hospital Clinic, Barcelona, Spain
k University of Melbourne, The Florey Institute of Neuroscience and Mental HealthVIC, Australia
l Department of Clinical Sciences, Clinical Memory Research Unit, Lund University, Lund, Sweden
m Department of Clinical Chemistry, Neurochemistry Laboratory and Biobank, Amsterdam Neuroscience, Amsterdam University Medical Centers, Amsterdam, Netherlands
n Department of Neurology, University of California, San Diego, CA, USA
o Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, United States
p Department of Neurology and Goizueta Alzheimer Disease Research Center, Emory University, Atlanta, United States
q Division of Neuroscience, National Institute on Aging, MD, Bethesda, United States

Abstract
The coronavirus disease 2019 (COVID-19) pandemic led to an abrupt halt of many Alzheimer’s disease (AD) research studies at sites spanning the world. This is especially true for studies requiring in-person contact, such as studies collecting biofluids. Since COVID-19 is likely to remain a threat for an extended period, the resumption of fluid biomarker studies requires the development and implementation of procedures that minimize the risk of in-person visits to participants, staff, and individuals handling the biofluid samples. Some issues to consider include structuring the visit workflow to minimize contacts and promote social distancing; screening and/or testing participants and staff for COVID-19; wearing masks and performing hand hygiene; and precautions for handling, storing, and analyzing biofluids. AD fluid biomarker research remains a vitally important public health priority and resuming studies requires appropriate safety procedures to protect research participants and staff.

Author Keywords
Alzheimer’s disease;  biofluids;  biomarkers;  COVID-19;  safety

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

“Targeting Alzheimer’s Disease in the Preclinical Stage” (2019) Alzheimer’s and Dementia

Targeting Alzheimer’s Disease in the Preclinical Stage
(2019) Alzheimer’s and Dementia, . 

McDade, E.a , Hake, A.M.b c , Bain, L.J.d , Carrillo, M.e

a Washington University School of Medicine, St. Louis, MO, United States
b Eli Lilly and Company, Indianapolis, IN, United States
c Indiana University School of Medicine, Indianapolis, IN, United States
d Elverson, PA, United States
e Division of Medical & Scientific Relations, Alzheimer’s Association, Chicago, IL, United States

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