List of publications for the week of March 15, 2021
Diffusion histology imaging differentiates distinct pediatric brain tumor histology
(2021) Scientific Reports, 11 (1), art. no. 4749, .
Ye, Z.a , Srinivasa, K.b , Meyer, A.c , Sun, P.a , Lin, J.a f , Viox, J.D.a g , Song, C.d , Wu, A.T.d , Song, S.-K.a d , Dahiya, S.b , Rubin, J.B.c e
a Department of Radiology, Washington University School of Medicine, Room 3221, 4525 Scott Ave., St. Louis, MO 63110, United States
b Department of Pathology and Immunology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, United States
c Department of Pediatrics, St. Louis Children’s Hospital, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, United States
d Department of Biomedical Engineering, Washington University, St. Louis, MO 63130, United States
e Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
f Keck School of Medicine, University of Southern California, Los Angeles, CA 9003389, United States
g School of Medicine, University of Missouri – Kansas City, Kansas City, MO 64110, United States
Abstract
High-grade pediatric brain tumors exhibit the highest cancer mortality rates in children. While conventional MRI has been widely adopted for examining pediatric high-grade brain tumors clinically, accurate neuroimaging detection and differentiation of tumor histopathology for improved diagnosis, surgical planning, and treatment evaluation, remains an unmet need in their clinical management. We employed a novel Diffusion Histology Imaging (DHI) approach employing diffusion basis spectrum imaging (DBSI) derived metrics as the input classifiers for deep neural network analysis. DHI aims to detect, differentiate, and quantify heterogeneous areas in pediatric high-grade brain tumors, which include normal white matter (WM), densely cellular tumor, less densely cellular tumor, infiltrating edge, necrosis, and hemorrhage. Distinct diffusion metric combination would thus indicate the unique distributions of each distinct tumor histology features. DHI, by incorporating DBSI metrics and the deep neural network algorithm, classified pediatric tumor histology with an overall accuracy of 85.8%. Receiver operating analysis (ROC) analysis suggested DHI’s great capability in distinguishing individual tumor histology with AUC values (95% CI) of 0.984 (0.982–0.986), 0.960 (0.956–0.963), 0.991 (0.990–0.993), 0.950 (0.944–0.956), 0.977 (0.973–0.981) and 0.976 (0.972–0.979) for normal WM, densely cellular tumor, less densely cellular tumor, infiltrating edge, necrosis and hemorrhage, respectively. Our results suggest that DBSI-DNN, or DHI, accurately characterized and classified multiple tumor histologic features in pediatric high-grade brain tumors. If these results could be further validated in patients, the novel DHI might emerge as a favorable alternative to the current neuroimaging techniques to better guide biopsy and resection as well as monitor therapeutic response in patients with high-grade brain tumors. © 2021, The Author(s).
Funding details
National Institutes of HealthNIHR01-NS047592
Office of Extramural Research, National Institutes of HealthOER
Office of Research Infrastructure Programs, National Institutes of HealthORIP, NIH, NIH-ORIP, ORIP
Document Type: Article
Publication Stage: Final
Source: Scopus
Cognitively normal APOE ε4 carriers have specific elevation of CSF SNAP-25
(2021) Neurobiology of Aging, 102, pp. 64-72.
Butt, O.H.a , Long, J.M.a d e , Henson, R.L.a d , Herries, E.a d , Sutphen, C.L.a d , Fagan, A.M.a d e , Cruchaga, C.c d e , Ladenson, J.H.f , Holtzman, D.M.a d e , Morris, J.C.a d e f , Ances, B.M.a b d e , Schindler, S.E.a d , for the Alzheimer’s Disease Neuroimaging Initiativeg
a Department of Neurology, Washington University, Saint Louis, MO, United States
b Department of Radiology, Washington University, Saint Louis, MO, United States
c Department of Psychiatry, Washington University, Saint Louis, MO, United States
d Knight Alzheimer Disease Research Center, Washington University, St. Louis, MO, United States
e Hope Center for Neurological Disorders, Washington University, St. Louis, MO, United States
f Department of Pathology and Immunology, Washington University, Saint Louis, MO, United States
Abstract
Cerebrospinal fluid (CSF) synaptosomal-associated protein 25 (SNAP-25) and neurogranin (Ng) are recently described biomarkers for pre- and postsynaptic integrity known to be elevated in symptomatic Alzheimer disease (AD). Their relationship with Apolipoprotein E (APOE) ε4 carrier status, the major genetic risk factor for AD, remains unclear. In this study, CSF SNAP-25 and Ng were compared in cognitively normal APOE ε4 carriers and noncarriers (n = 274, mean age 65 ± 9.0 years, 39% APOE ε4 carriers, 58% female). CSF SNAP-25, not CSF Ng, was specifically elevated in APOE ε4 carriers versus noncarriers (5.95 ± 1.72 pg/mL, 4.44 ± 1.40 pg/mL, p < 0.0001), even after adjusting for age, sex, years of education, and amyloid status (p < 0.0001). CSF total tau (t-tau), phosphorylated-tau-181 (ptau181), and neurofilament light chain (NfL) also did not vary by APOE ε4 status. Our findings suggest APOE ε4 carriers have amyloid-related and amyloid-independent presynaptic disruption as reflected by elevated CSF SNAP-25 levels. In contrast, postsynaptic disruption as reflected by elevations in CSF neurogranin is related to amyloid status. © 2021 Elsevier Inc.
Author Keywords
APOE; Biomarker; CSF; Neurogranin; SNAP-25; Synapse
Funding details
Johnson and JohnsonJ&J
National Institute on AgingNIAK23AG053426, R03AG050921, P01 AG026276
Janssen Research and DevelopmentJRD
National Institutes of HealthNIHU01 AG024904
Fujirebio US
University of Southern CaliforniaUSC
U.S. Department of DefenseDODW81XWH-12-2-0012
GE Healthcare
H. Lundbeck A/S
Hope Center for Neurological Disorders
Genentech
National Institute of Biomedical Imaging and BioengineeringNIBIB
Northern California Institute for Research and EducationNCIRE
Alzheimer’s Disease Neuroimaging InitiativeADNI
Merck
IXICO
Document Type: Article
Publication Stage: Final
Source: Scopus
Long runs of homozygosity are associated with Alzheimer’s disease
(2021) Translational Psychiatry, 11 (1), art. no. 142, .
Moreno-Grau, S.a b , Fernández, M.V.c d , de Rojas, I.a b , Garcia-González, P.a , Hernández, I.a , Farias, F.c d , Budde, J.P.c d , Quintela, I.e , Madrid, L.f , González-Pérez, A.f , Montrreal, L.a , Alarcón-Martín, E.a , Alegret, M.a , Maroñas, O.e , Pineda, J.A.g , Macías, J.g , Abdelnour, C.a b , Aguilera, N.a , Alarcón-Martín, E.a , Alegret, M.a b , Benaque, A.a , Boada, M.a b , Buendía, M.a , Cañabate, P.a b , Carracedo, A.e z , Corbatón, A.aa , de Rojas, I.a , Diego, S.a , Espinosa, A.a b , Gailhajenet, A.a , García González, P.a , Gil, S.a , Guitart, M.a , González Pérez, A.f , Hernández, I.a b , Ibarria, M.a , Lafuente, A.a , Macías, J.g , Maroñas, O.d , Martín, E.a , Martínez, M.T.aa , Marquié, M.a , Mauleón, A.a , Monté-Rubio, G.a , Montrreal, L.a , Moreno-Grau, S.a b , Moreno, M.a , Orellana, A.a , Ortega, G.a b , Pancho, A.a , Pelejà, E.a , Pérez-Cordon, A.a , Pineda, J.A.h , Preckler, S.a , Quintela, I.e , Real, L.M.g r , Rodríguez-Gómez, O.a b , Rosende-Roca, M.a , Ruiz, A.a b , Ruiz, S.a b , Sáez, M.E.f , Sanabria, A.a b , Santos-Santos, M.A.a , Serrano-Ríos, M.aa ab , Sotolongo-Grau, O.a , Tárraga, L.a b , Valero, S.a b , Vargas, L.a , Adarmes-Gómez, A.D.b t , Alarcón-Martín, E.a , Álvarez, I.l , Álvarez, V.n o , Amer-Ferrer, G.ac , Antequera, M.y , Antúnez, C.y , Baquero, M.ad , Bernal, M.s , Blesa, R.b h , Boada, M.a b , Buiza-Rueda, D.b t , Bullido, M.J.b i n , Burguera, J.A.ad , Calero, M.b u v , Carrillo, F.b t , Carrión-Claro, M.b t , Casajeros, M.J.k , Clarimón, J.b h , Cruz-Gamero, J.M.r , de Pancorbo, M.M.ae , de Rojas, I.a b , del Ser, T.j , Diez-Fairen, M.l , Fortea, J.b h , Franco, E.s , Frank-García, A.b j af , García-Alberca, J.M.q , García Madrona, S.v , Garcia-Ribas, G.k , Gómez-Garre, P.b t , Hernández, I.a b , Hevilla, S.q , Jesús, S.b t , Labrador Espinosa, M.A.b t , Lage, C.b m , Legaz, A.as , Lleó, A.b h , López de Munáin, A.ag , López-García, S.b m , Macías, D.b t , Manzanares, S.y ah , Marín, M.s , Marín-Muñoz, J.y , Marín, T.q , Marquié, M.a b , Martín-Montes, A.b i af , Martínez, B.y , Martínez, C.o ai , Martínez, V.y , Martínez-Lage Álvarez, P.aj , Medina, M.b u , Mendioroz Iriarte, M.ak , Menéndez-González, M.o al , Mir, P.b t , Molinuevo, J.L.am , Montrreal, L.a , Moreno-Grau, S.a b , Orellana, A.a , Pastor, A.B.u , Pastor, P.l , Pérez-Tur, J.b an ao , Periñán-Tocino, T.b t , Piñol-Ripoll, G.b p , Rábano, A.b u w , Real de Asúa, D.ap , Rodrigo, S.s , Rodríguez-Rodríguez, E.b m , Royo, J.L.r , Ruiz, A.a b , Sanchez del Valle Díaz, R.aq , Sánchez-Juan, P.b m , Sastre, I.b s , Sotolongo-Grau, O.a , Tárraga, L.a b , Valero, S.a b , Vicente, M.P.y , Vivancos, L.y , Marquié, M.a b , Valero, S.a b , Benaque, A.a , Clarimón, J.b h , Bullido, M.J.b i j , García-Ribas, G.k , Pástor, P.l , Sánchez-Juan, P.b m , Álvarez, V.n o , Piñol-Ripoll, G.b p , García-Alberca, J.M.q , Royo, J.L.r , Franco-Macías, E.s , Mir, P.b t , Calero, M.b u v , Medina, M.b u , Rábano, A.b u w , Ávila, J.b x , Antúnez, C.y , Real, L.M.g r , Orellana, A.a , Carracedo, Á.e z , Sáez, M.E.f , Tárraga, L.a b , Boada, M.a b , Cruchaga, C.c d , Ruiz, A.a b , The GR@ACE study groupar , DEGESCO consortiumar , for the Alzheimer’s Disease Neuroimaging Initiativeas
a Research Center and Memory clinic Fundació ACE. Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain
b CIBERNED, Center for Networked Biomedical Research on Neurodegenerative Diseases, Carlos III Institute of Health, Madrid, Spain
c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
d Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
e Grupo de Medicina Xenómica, Centro Nacional de Genotipado (CEGEN-PRB3-ISCIII), Universidade de Santiago de Compostela, Santiago de Compostela, Spain
f CAEBI. Centro Andaluz de Estudios Bioinformáticos, Sevilla, Spain
g Unidad Clínica de Enfermedades Infecciosas y Microbiología. Hospital Universitario de Valme, Sevilla, Spain
h Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
i Centro de Biología Molecular Severo Ochoa (C.S.I.C.-U.A.M.), Universidad Autónoma de Madrid, Madrid, Spain
j Instituto de Investigación Sanitaria “Hospital la Paz” (IdIPaz), Madrid, Spain
k Hospital Universitario Ramón y Cajal, Madrid, Spain
l Fundació per la Recerca Biomèdica i Social Mútua Terrassa, and Memory Disorders Unit, Department of Neurology, Hospital Universitari Mútua de Terrassa, University of Barcelona School of Medicine, Terrassa, Barcelona, Spain
m Neurology Service “Marqués de Valdecilla” University Hospital (University of Cantabria and IDIVAL), Santander, Spain
n Laboratorio de Genética Hospital Universitario Central de Asturias, Oviedo, Spain
o Instituto de Investigación Biosanitaria del Principado de Asturias (ISPA), Oviedo, Spain
p Unitat Trastorns Cognitius, Hospital Universitari Santa Maria de Lleida, Institut de Recerca Biomédica de Lleida (IRBLLeida), Lleida, Spain
q Alzheimer Research Center & Memory Clinic, Andalusian Institute for Neuroscience, Málaga, Spain
r Dep. of Surgery, Biochemistry and Molecular Biology, School of Medicine, University of Málaga, Málaga, Spain
s Unidad de Demencias, Servicio de Neurología y Neurofisiología. Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
t Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología. Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
u CIEN Foundation, Queen Sofia Foundation Alzheimer Center, Madrid, Spain
v Instituto de Salud Carlos III (ISCIII), Madrid, Spain
w BT-CIEN, Madrid, Spain
x Department of Molecular Neuropathology, Centro de Biología Molecular “Severo Ochoa” (CBMSO), Consejo Superior de Investigaciones Científicas (CSIC)/Universidad Autónoma de Madrid (UAM), Madrid, Spain
y Unidad de Demencias, Hospital Clínico Universitario Virgen de la Arrixaca, Madrid, Spain
z Fundación Pública Galega de Medicina Xenómica- CIBERER-IDIS, Santiago de Compostela, Spain
aa Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, Madrid, Spain
ab Hospital Clínico San Carlos, Madrid, Spain
ac Department of Neurology, Hospital Universitario Son Espases, Palma, Spain
ad Servei de Neurologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain
ae BIOMICs, País Vasco; Centro de Investigación Lascaray. Universidad del País Vasco UPV/EHU, Vitori-Gasteiz, Spain
af Neurology Service, Hospital Universitario La Paz (UAM), Madrid, Spain
ag Hospital Donostia de San Sebastián, San Sebastián, Spain
ah Fundación para la Formación e Investigación Sanitarias de la Región de Murcia, Murcia, Spain
ai Servicio de Neurología-Hospital de Cabueñes-Gijón, Gijón, Spain
aj Centro de Investigación y Terapias Avanzadas. Fundación CITA-alzheimer, San Sebastián, Spain
ak Navarrabiomed, Pamplona, Spain
al Servicio de Neurología -Hospital Universitario Central de Asturias, Oviedo, Spain
am Barcelona βeta Brain Research Center – Fundació Pasqual Maragall, Barcelona, Spain
an Unitat de Genètica Molecular. Institut de Biomedicina de València-CSIC, Valencia, Spain
ao Unidad Mixta de Neurologia Genètica. Instituto de Investigación Sanitaria La Fe, Valencia, Spain
ap Hospital Universitario La Princesa, Madrid, Spain
aq Hospital Clínic Barcelona, Barcelona, Spain
Abstract
Long runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimer’s disease (AD); however, their search has been poorly assessed to date. To investigate homozygosity in AD, here we performed a fine-scale ROH analysis using 10 independent cohorts of European ancestry (11,919 AD cases and 9181 controls.) We detected an increase of homozygosity in AD cases compared to controls [βAVROH (CI 95%) = 0.070 (0.037–0.104); P = 3.91 × 10−5; βFROH (CI95%) = 0.043 (0.009–0.076); P = 0.013]. ROHs increasing the risk of AD (OR > 1) were significantly overrepresented compared to ROHs increasing protection (p < 2.20 × 10−16). A significant ROH association with AD risk was detected upstream the HS3ST1 locus (chr4:11,189,482‒11,305,456), (β (CI 95%) = 1.09 (0.48 ‒ 1.48), p value = 9.03 × 10−4), previously related to AD. Next, to search for recessive candidate variants in ROHs, we constructed a homozygosity map of inbred AD cases extracted from an outbred population and explored ROH regions in whole-exome sequencing data (N = 1449). We detected a candidate marker, rs117458494, mapped in the SPON1 locus, which has been previously associated with amyloid metabolism. Here, we provide a research framework to look for recessive variants in AD using outbred populations. Our results showed that AD cases have enriched homozygosity, suggesting that recessive effects may explain a proportion of AD heritability. © 2021, The Author(s).
Funding details
National Institutes of HealthNIHP01AG003991, R01AG044546, R01AG057777, R01AG058501, RF1AG053303, U01AG058922
Alzheimer’s AssociationAAAARG-16-441560, BAND-14-338165, BFG-15-362540, NIRG-11-200110
Document Type: Article
Publication Stage: Final
Source: Scopus
Effects of anticholinergic medication use on brain integrity in persons living with HIV and persons without HIV
(2021) AIDS (London, England), 35 (3), pp. 381-391.
Cooley, S.A.a , Paul, R.H.b , Strain, J.F.a , Boerwinkle, A.a , Kilgore, C.a , Ances, B.M.a c d
a Department of Neurology, Washington University in Saint Louis
b Department of Psychology, University of MissouriSaint Louis, Seychelles
c Department of Radiology
d Hope Center for Neurological Disorders, Washington University in Saint Louis, Saint Louis, Missouri, USA
Abstract
OBJECTIVE: This study examined relationships between anticholinergic medication burden and brain integrity in people living with HIV (PLWH) and people without HIV (HIV-). METHODS: Neuropsychological performance z-scores (learning, retention, executive function, motor/psychomotor speed, language domains, and global cognition), and neuroimaging measures (brain volumetrics and white matter fractional anisotropy) were analyzed in PLWH (n = 209) and HIV- (n = 95) grouped according to the Anticholinergic Cognitive Burden (ACB) scale (0 = no burden, 1-3 = low burden, >3 = high burden). Neuropsychological performance and neuroimaging outcomes were compared between HIV- and PLWH with high anticholinergic burden. Within a cohort of PLWH (n = 90), longitudinal change in ACB score over ∼2 years was correlated to the rate of change per month of study interval in neuropsychological performance and neuroimaging measures. RESULTS: A higher number of anticholinergic medications and ACB was observed in PLWH compared with HIV- (P < 0.05). A higher ACB was associated with worse motor/psychomotor performance, smaller occipital lobe, putamen, subcortical gray matter and total gray matter volumes in HIV-; and poorer executive function, retention and global cognition, smaller brain volumes (frontal, parietal and temporal lobes, hippocampus, amygdala, cortex, subcortical gray matter and total gray matter), and reduced fractional anisotropy (posterior corpus callosum, perforant pathway) in PLWH. PLWH with high anticholinergic burden performed worse on tests of learning and executive function compared with HIV- with high anticholinergic burden. Longitudinally, PLWH who reduced their ACB over time had better neuropsychological performance and neuroimaging measures. CONCLUSION: Anticholinergic medications were associated with worse neuropsychological performance and reduced structural brain integrity, and these effects were more widespread in PLWH. Use of anticholinergic medications should be carefully monitored in older adults with deprescription considered whenever possible. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
Document Type: Article
Publication Stage: Final
Source: Scopus
Microglia control small vessel calcification via TREM2
(2021) Science Advances, 7 (9), art. no. eabc4898, .
Zarb, Y.a b i , Sridhar, S.a b , Nassiri, S.c , Utz, S.G.d , Schaffenrath, J.a b , Maheshwari, U.a b , Rushing, E.J.e , Peter Nilsson, K.R.f , Delorenzi, M.c g , Colonna, M.h , Greter, M.d , Keller, A.a b
a Department of Neurosurgery, Clinical Neurocentre, Zurich University Hospital, Zurich University, Zürich, Switzerland
b Neuroscience Center Zurich, University of Zurich, ETH Zurich, Zurich, Switzerland
c Bioinformatics Core Facility, Swiss Institute of Bioinformatics, Lausanne, Switzerland
d Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
e Institute of Neuropathology, Zurich University Hospital, Zurich, Switzerland
f Department of Chemistry, Linköping University, Linköping, Sweden
g Department of Oncology, University Lausanne, Lausanne, Switzerland
h Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
i Institute of Physiological Genomics, Biomedical Center, Ludwig-Maximilians-University Munich, Munich, Germany
Abstract
Microglia participate in central nervous system (CNS) development and homeostasis and are often implicated in modulating disease processes. However, less is known about the role of microglia in the biology of the neurovascular unit (NVU). In particular, data are scant on whether microglia are involved in CNS vascular pathology. In this study, we use a mouse model of primary familial brain calcification, Pdgfbret/ret, to investigate the role of microglia in calcification of the NVU. We report that microglia enclosing vessel calcifications, coined calcification-associated microglia, display a distinct activation phenotype. Pharmacological ablation of microglia with the CSF1R inhibitor PLX5622 leads to aggravated vessel calcification. Mechanistically, we show that microglia require functional TREM2 for controlling vascular calcification. Our results demonstrate that microglial activity in the setting of pathological vascular calcification is beneficial. In addition, we identify a previously unrecognized function of microglia in halting the expansion of vascular calcification. Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
Funding details
Horizon 2020819229
FK-16-034
Stiftung Synapsis – Alzheimer Forschung Schweiz AFS
Fondation Leducq14CVD02
European Research CouncilERC
Krebsliga SchweizKLS-3848-02-2016
2019-PI02
Universität ZürichUZH
Schweizerische Herzstiftung
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen ForschungSNF31003A_159514, BSGI0_155832, 310030_188952, PP00P3_170626
Document Type: Article
Publication Stage: Final
Source: Scopus
Tract-Specific Relationships Between Cerebrospinal Fluid Biomarkers and Periventricular White Matter in Posthemorrhagic Hydrocephalus of Prematurity
(2021) Neurosurgery, 88 (3), pp. 698-706.
Morales, D.M.a , Smyser, C.D.b c d , Han, R.H.a , Kenley, J.K.b , Shimony, J.S.c , Smyser, T.A.e , Strahle, J.M.a d , Inder, T.E.f , Limbrick, D.D.a d
a Department 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 Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
f Department of Pediatric Newborn Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, MA
Abstract
BACKGROUND: Posthemorrhagic hydrocephalus (PHH) is associated with neurological morbidity and complex neurosurgical care. Improved tools are needed to optimize treatments and to investigate the developmental sequelae of PHH. OBJECTIVE: To examine the relationship between diffusion magnetic resonance imaging (dMRI) and cerebrospinal fluid (CSF) biomarkers of PHH. METHODS: A total of 14 preterm (PT) infants with PHH and 46 controls were included. PT CSF was collected at temporizing surgery in PHH infants (PHH PT CSF) or lumbar puncture in controls. Term-equivalent age (TEA) CSF was acquired via implanted device or at permanent CSF diversion surgery in PHH (PHH-TEA-CSF) or lumbar puncture in controls. TEA dMRI scans were used to measure fractional anisotropy (FA) and mean diffusivity (MD) in the genu of corpus callosum (gCC), posterior limb of internal capsule (PLIC), and optic radiations (OPRA). Associations between dMRI measures and CSF amyloid precursor protein (APP), neural cell adhesion-1 (NCAM-1), and L1 cell adhesion molecule (L1CAM) were assessed using Pearson correlations. RESULTS: APP, NCAM-1, and L1CAM were elevated over controls in PHH-PT-CSF and PHH-TEA-CSF. dMRI FA and MD differed between control and PHH infants across all tracts. PHH-PT-CSF APP levels correlated with gCC and OPRA FA and PLIC MD, while L1CAM correlated with gCC and OPRA FA. In PHH-TEA-CSF, only L1CAM correlated with OPRA MD. CONCLUSION: Tract-specific associations were observed between dMRI and CSF biomarkers at the initiation of PHH treatment. dMRI and CSF biomarker analyses provide innovative complementary methods for examining PHH-related white matter injury and associated developmental sequelae. Copyright © 2020 by the Congress of Neurological Surgeons.
Author Keywords
Biomarker; Cerebrospinal fluid; Diffusion MRI, Intraventricular hemorrhage; Diffusion tensor imaging; MRI; Periventricular white matter; Posthemorrhagic hydrocephalus; Preterm
Document Type: Article
Publication Stage: Final
Source: Scopus
Non-invasive quantification of inflammation, axonal and myelin injury in multiple sclerosis
(2021) Brain: A Journal of Neurology, 144 (1), pp. 213-223.
Schiavi, S.a b c , Petracca, M.a , Sun, P.d , Fleysher, L.e , Cocozza, S.a f , El Mendili, M.M.a , Signori, A.g , Babb, J.S.h , Podranski, K.a , Song, S.-K.d i j k , Inglese, M.a b c
a Department of Neurology, Icahn School of Medicine at Mount Sinai, NY, NY, United States
b Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Italy
c Ospedale Policlinico San Martino-IRCCS, Genoa, Italy
d Radiology, Washington University School of Medicine, St. Louis, MO, USA
e Department of Radiology, Icahn School of Medicine at Mount Sinai, NY, NY, United States
f Department of Advanced Biomedical Sciences, University of Naples “Federico II”, Naples, Italy
g Department of Health Sciences, University of Genoa, Genoa, Italy
h Department of Radiology, Center for Biomedical Imaging, New York University, Langone Medical CenterNY, United States
i Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
j Biomedical Engineering, Washington University, St. Louis, MO, USA
k Biomedical MR Laboratory, Washington University School of Medicine, St. Louis, MO, USA
Abstract
The aim of this study was to determine the feasibility of diffusion basis spectrum imaging in multiple sclerosis at 7 T and to investigate the pathological substrates of tissue damage in lesions and normal-appearing white matter. To this end, 43 patients with multiple sclerosis (24 relapsing-remitting, 19 progressive), and 21 healthy control subjects were enrolled. White matter lesions were classified in T1-isointense, T1-hypointense and black holes. Mean values of diffusion basis spectrum imaging metrics (fibres, restricted and non-restricted fractions, axial and radial diffusivities and fractional anisotropy) were measured from whole brain white matter lesions and from both lesions and normal appearing white matter of the corpus callosum. Significant differences were found between T1-isointense and black holes (P ranging from 0.005 to <0.001) and between lesions’ centre and rim (P < 0.001) for all the metrics. When comparing the three subject groups in terms of metrics derived from corpus callosum normal appearing white matter and T2-hyperintense lesions, a significant difference was found between healthy controls and relapsing-remitting patients for all metrics except restricted fraction and fractional anisotropy; between healthy controls and progressive patients for all metrics except restricted fraction and between relapsing-remitting and progressive multiple sclerosis patients for all metrics except fibres and restricted fractions (P ranging from 0.05 to <0.001 for all). Significant associations were found between corpus callosum normal-appearing white matter fibres fraction/non-restricted fraction and the Symbol Digit Modality Test (respectively, r = 0.35, P = 0.043; r = -0.35, P = 0.046), and between black holes radial diffusivity and Expanded Disability Status Score (r = 0.59, P = 0.002). We showed the feasibility of diffusion basis spectrum imaging metrics at 7 T, confirmed the role of the derived metrics in the characterization of lesions and normal appearing white matter tissue in different stages of the disease and demonstrated their clinical relevance. Thus, suggesting that diffusion basis spectrum imaging is a promising tool to investigate multiple sclerosis pathophysiology, monitor disease progression and treatment response. © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.
Author Keywords
axonal injury; diffusion basis spectrum imaging; inflammation; multiple sclerosis
Document Type: Article
Publication Stage: Final
Source: Scopus
Alzheimer’s disease alters oligodendrocytic glycolytic and ketolytic gene expression
(2021) Alzheimer’s and Dementia, .
Saito, E.R.a , Miller, J.B.b , Harari, O.c , Cruchaga, C.c d e f , Mihindukulasuriya, K.A.g , Kauwe, J.S.K.b , Bikman, B.T.a
a Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT, United States
b Department of Biology, Brigham Young University, Provo, UT, United States
c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
e Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
f NeuroGenomics and Informatics, Washington University School of Medicine, St. Louis, MO, United States
g The Edison Family Center for Genome Sciences and Systems Biology, Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Introduction: Sporadic Alzheimer’s disease (AD) is strongly correlated with impaired brain glucose metabolism, which may affect AD onset and progression. Ketolysis has been suggested as an alternative pathway to fuel the brain. Methods: RNA-seq profiles of post mortem AD brains were used to determine whether dysfunctional AD brain metabolism can be determined by impairments in glycolytic and ketolytic gene expression. Data were obtained from the Knight Alzheimer’s Disease Research Center (62 cases; 13 controls), Mount Sinai Brain Bank (110 cases; 44 controls), and the Mayo Clinic Brain Bank (80 cases; 76 controls), and were normalized to cell type: astrocytes, microglia, neurons, oligodendrocytes. Results: In oligodendrocytes, both glycolytic and ketolytic pathways were significantly impaired in AD brains. Ketolytic gene expression was not significantly altered in neurons, astrocytes, and microglia. Discussion: Oligodendrocytes may contribute to brain hypometabolism observed in AD. These results are suggestive of a potential link between hypometabolism and dysmyelination in disease physiology. Additionally, ketones may be therapeutic in AD due to their ability to fuel neurons despite impaired glycolytic metabolism. © 2021 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
Alzheimer’s disease; astrocytes; glycolysis; ketolysis; metabolic RNA-seq profiles; microglia; neurons; oligodendrocytes
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Autoimmune encephalitis: Proposed best practice recommendations for diagnosis and acute management
(2021) Journal of Neurology, Neurosurgery and Psychiatry, .
Abboud, H.a b , Probasco, J.C.c , Irani, S.d , Ances, B.e , Benavides, D.R.f , Bradshaw, M.g h , Christo, P.P.i , Dale, R.C.j , Fernandez-Fournier, M.k , Flanagan, E.P.l , Gadoth, A.m , George, P.n , Grebenciucova, E.o , Jammoul, A.n , Lee, S.-T.p , Li, Y.n , Matiello, M.q r , Morse, A.M.s , Rae-Grant, A.n , Rojas, G.t u , Rossman, I.v , Schmitt, S.w , Venkatesan, A.c , Vernino, S.x , Pittock, S.J.l , Titulaer, M.J.y
a Neurology, Case Western Reserve University, Cleveland, OHO, United States
b Multiple Sclerosis and Neuroimmunology Program, University Hospitals of Cleveland, Cleveland, OHO, United States
c Neurology, Johns Hopkins Medicine, Baltimore, MD, United States
d Oxford Autoimmune Neurology Group, John Radcliffe Hospital, Oxford, United Kingdom
e Neurology, Washington University in St Louis, St Louis, MO, United States
f Neurology, University of Maryland, School of Medicine, Baltimore, MD, United States
g Neurology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
h Billings Clinic, Billings, MT, United States
i Neurology, Minas Gerais Federal University, Risoleta Tolentino Neves Hospital, Belo Horizonte, MG, Brazil
j Neuroimmunology Group, University of Sydney, Faculty of Medicine and Health, Sydney, NSW, Australia
k Neurology, La Paz University Hospital, General Hospital, Department of Neurology, Madrid, Spain
l Neurology, Mayo Clinic, Rochester, MN, United States
m Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
n Neurology, Cleveland Clinic, Cleveland, OH, United States
o Northwestern University, Feinberg School of Medicine, Chicago, IL, United States
p Neurology, Seoul National University, College of Medicine, Seoul, South Korea
q Neurology, Massachusetts General Hospital, Boston, MA, United States
r Neurology, Harvard Medical School, Boston, MA, United States
s Pediatric Neurology, Geisinger Commonwealth School of Medicine, Scranton, PA, United States
t Neurology, Sanatorio de la Trinidad Mitre, Buenos Aires, Argentina
u Neurology, Favaloro Foundation, Buenos Aires, Argentina
v Neuro-developmental Science Center, Akron Children’s Hospital, Akron, OH, United States
w Neurology, MUSC, Charleston, SC, United States
x Neurology, UT Southwestern, Dallas, TX, United States
y Neurology, Erasmus Medical Center, Zuid-Holland Rotterdam, Netherlands
Abstract
The objective of this paper is to evaluate available evidence for each step in autoimmune encephalitis management and provide expert opinion when evidence is lacking. The paper approaches autoimmune encephalitis as a broad category rather than focusing on individual antibody syndromes. Core authors from the Autoimmune Encephalitis Alliance Clinicians Network reviewed literature and developed the first draft. Where evidence was lacking or controversial, an electronic survey was distributed to all members to solicit individual responses. Sixty-eight members from 17 countries answered the survey. Corticosteroids alone or combined with other agents (intravenous IG or plasmapheresis) were selected as a first-line therapy by 84% of responders for patients with a general presentation, 74% for patients presenting with faciobrachial dystonic seizures, 63% for NMDAR-IgG encephalitis and 48.5% for classical paraneoplastic encephalitis. Half the responders indicated they would add a second-line agent only if there was no response to more than one first-line agent, 32% indicated adding a second-line agent if there was no response to one first-line agent, while only 15% indicated using a second-line agent in all patients. As for the preferred second-line agent, 80% of responders chose rituximab while only 10% chose cyclophosphamide in a clinical scenario with unknown antibodies. Detailed survey results are presented in the manuscript and a summary of the diagnostic and therapeutic recommendations is presented at the conclusion. © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Author Keywords
autoimmune encephalitis; neuroimmunology; paraneoplastic syndrome
Document Type: Review
Publication Stage: Article in Press
Source: Scopus
Neuromodulation by the immune system: a focus on cytokines
(2021) Nature Reviews Immunology, .
Salvador, A.F.a b , de Lima, K.A.a , Kipnis, J.a
a Center for Brain Immunology and Glia (BIG), Department of Pathology & Immunology, Washington University School of Medicine in St. Louis, St Louis, MO, United States
b Neuroscience Graduate Program, University of Virginia, Charlottesville, VA, United States
Abstract
Interactions between the immune system and the nervous system have been described mostly in the context of diseases. More recent studies have begun to reveal how certain immune cell-derived soluble effectors, the cytokines, can influence host behaviour even in the absence of infection. In this Review, we contemplate how the immune system shapes nervous system function and how it controls the manifestation of host behaviour. Interactions between these two highly complex systems are discussed here also in the context of evolution, as both may have evolved to maximize an organism’s ability to respond to environmental threats in order to survive. We describe how the immune system relays information to the nervous system and how cytokine signalling occurs in neurons. We also speculate on how the brain may be hardwired to receive and process information from the immune system. Finally, we propose a unified theory depicting a co-evolution of the immune system and host behaviour in response to the evolutionary pressure of pathogens. © 2021, Springer Nature Limited.
Document Type: Review
Publication Stage: Article in Press
Source: Scopus
Transpupillary two-photon in vivo imaging of the mouse retina
(2021) Journal of Visualized Experiments, 2021 (168), art. no. e61970, pp. 1-23.
Wang, Z.a b , McCracken, S.a b , Williams, P.R.a c d
a John F. Hardesty, MD Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, United States
b Washington University School of Medicine, United States
c Department of Neuroscience, Washington University School of Medicine, United States
d Hope Center for Neurological Disorders, Washington University School of Medicine, United States
Abstract
The retina transforms light signals from the environment into electrical signals that are propagated to the brain. Diseases of the retina are prevalent and cause visual impairment and blindness. Understanding how such diseases progress is critical to formulating new treatments. In vivo microscopy in animal models of disease is a powerful tool for understanding neurodegeneration and has led to important progress towards treatments of conditions ranging from Alzheimer’s disease to stroke. Given that the retina is the only central nervous system structure inherently accessible by optical approaches, it naturally lends itself towards in vivo imaging. However, the native optics of the lens and cornea present some challenges for effective imaging access. This protocol outlines methods for in vivo two-photon imaging of cellular cohorts and structures in the mouse retina at cellular resolution, applicable for both acuteand chronic-duration imaging experiments. It presents examples of retinal ganglion cell (RGC), amacrine cell, microglial, and vascular imaging using a suite of labeling techniques including adeno-associated virus (AAV) vectors, transgenic mice, and inorganic dyes. Importantly, these techniques extend to all cell types of the retina, and suggested methods for accessing other cellular populations of interest are described. Also detailed are example strategies for manual image postprocessing for display and quantification. These techniques are directly applicable to studies of retinal function in health and disease. © 2021 JoVE Creative Commons Attribution.
Funding details
BrightFocus FoundationBFF
T32 EY013360
Research to Prevent BlindnessRPB
Document Type: Article
Publication Stage: Final
Source: Scopus
Neuroimaging the Neuropathogenesis of HIV
(2021) Current HIV/AIDS Reports, .
Boerwinkle, A.H., Meeker, K.L., Luckett, P., Ances, B.M.
Department of Neurology, Washington University in St. Louis, School of Medicine, Campus Box 8111, 660 South Euclid Avenue, St. Louis, MO 63110, United States
Abstract
Purpose of Review: This review highlights neuroimaging studies of HIV conducted over the last 2 years and discusses how relevant findings further our knowledge of the neuropathology of HIV. Three major avenues of neuroimaging research are covered with a particular emphasis on inflammation, aging, and substance use in persons living with HIV (PLWH). Recent Findings: Neuroimaging has been a critical tool for understanding the neuropathological underpinnings observed in HIV. Recent studies comparing levels of neuroinflammation in PLWH and HIV-negative controls show inconsistent results but report an association between elevated neuroinflammation and poorer cognition in PLWH. Other recent neuroimaging studies suggest that older PLWH are at increased risk for brain and cognitive compromise compared to their younger counterparts. Finally, recent findings also suggest that the effects of HIV may be exacerbated by alcohol and drug abuse. Summary: These neuroimaging studies provide insight into the structural, functional, and molecular changes occurring in the brain due to HIV. HIV triggers a strong neuroimmune response and may lead to a cascade of events including increased chronic inflammation and cognitive decline. These outcomes are further exacerbated by age and age-related comorbidities, as well as lifestyle factors such as drug use/abuse. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.
Author Keywords
Aging; HIV; Inflammation; Neuroimaging; Substance use
Document Type: Review
Publication Stage: Article in Press
Source: Scopus