Publications

Hope Center member publications

List of publications for the week of March 8, 2021

Application of electrical stimulation for peripheral nerve regeneration: Stimulation parameters and future horizons” (2021) Interdisciplinary Neurosurgery: Advanced Techniques and Case Management

Application of electrical stimulation for peripheral nerve regeneration: Stimulation parameters and future horizons
(2021) Interdisciplinary Neurosurgery: Advanced Techniques and Case Management, 24, art. no. 101117, . 

Javeed, S.a , Faraji, A.H.a , Dy, C.b , Ray, W.Z.a , MacEwan, M.R.a

a Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
b Division of Hand and Microsurgery, Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Peripheral nerve trauma impacts both social and occupational quality of life. Patients are typically young and subsequently suffer from lifelong disability. Unlike the central nervous system, the peripheral nervous system has the capacity to regenerate along previous or new connections. Yet, complete functional recovery has been an elusive clinical objective despite the development of advanced microsurgical techniques to repair nerves. In recent decades significant amount of work has expanded the focus towards establishing new facets of adjuvant treatment to improve nerve regeneration. One potential therapy is the application of electric stimulation of peripheral nerves immediately following microsurgical repair. Mounting pre-clinical and clinical evidence demonstrated the efficacy of electrical stimulation in improving nerve regeneration and functional recovery. In this paper, we review the potential therapeutic benefits of electrical stimulation and the current limitations of regeneration after nerve injury. We also summarize the proposed mechanisms of electrical stimulation in increasing the regenerative capacity of peripheral nerves, including evidence from human clinical trials. Finally, we discuss stimulation parameters and safety profiles with an eye towards future treatment strategies. Combining electrical stimulation with conductive scaffolds has the potential to improve successful nerve regeneration and may have profound clinical implications to nerve injury patients. © 2021 The Author(s)

Author Keywords
Axon guidance;  Axon regeneration;  Bioresorbable;  Electrical stimulation;  Nerve electrodes;  Nerve scaffolds;  Peripheral nerve injury

Document Type: Review
Publication Stage: Final
Source: Scopus

Natural oscillatory modes of 3D deformation of the human brain in vivo” (2021) Journal of Biomechanics

Natural oscillatory modes of 3D deformation of the human brain in vivo
(2021) Journal of Biomechanics, 119, art. no. 110259, . 

Escarcega, J.D.a , Knutsen, A.K.b , Okamoto, R.J.a , Pham, D.L.b , Bayly, P.V.a

a Mechanical Engineering and Materials Science, Washington University in St. LouisMO, United States
b Center for Neuroscience and Regenerative Medicine, Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, United States

Abstract
Natural modes and frequencies of three-dimensional (3D) deformation of the human brain were identified from in vivo tagged magnetic resonance images (MRI) acquired dynamically during transient mild acceleration of the head. Twenty 3D strain fields, estimated from tagged MRI image volumes in 19 adult subjects, were analyzed using dynamic mode decomposition (DMD). These strain fields represented dynamic, 3D brain deformations during constrained head accelerations, either involving rotation about the vertical axis of the neck or neck extension. DMD results reveal fundamental oscillatory modes of deformation at damped frequencies near 7 Hz (in neck rotation) and 11 Hz (in neck extension). Modes at these frequencies were found consistently among all subjects. These characteristic features of 3D human brain deformation are important for understanding the response of the brain in head impacts and provide valuable quantitative criteria for the evaluation and use of computer models of brain mechanics. © 2021 Elsevier Ltd

Author Keywords
Brain mechanics;  Dynamic mode decomposition;  Natural frequency;  Oscillations;  Tagged MRI;  Traumatic brain injury

Funding details
National Institutes of HealthNIHR01/R56 NS055951, U01 NS112120
Center for Neuroscience and Regenerative MedicineCNRM

Document Type: Article
Publication Stage: Final
Source: Scopus

Peripheral sensory stimulation elicits global slow waves by recruiting somatosensory cortex bilaterally” (2021) Proceedings of the National Academy of Sciences of the United States of America

Peripheral sensory stimulation elicits global slow waves by recruiting somatosensory cortex bilaterally
(2021) Proceedings of the National Academy of Sciences of the United States of America, 118 (8), art. no. e2021252118, . 

Rosenthal, Z.P.a b c , Raut, R.V.b d , Bowen, R.M.c e , Snyder, A.Z.c d , Culver, J.P.d e f , Raichle, M.E.c d e , Lee, J.-M.c d e

a Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO 63110, United States
b Graduate Program of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
d Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
e Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO 63110, United States
f Department of Physics, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Slow waves (SWs) are globally propagating, low-frequency (0.5- to 4-Hz) oscillations that are prominent during sleep and anesthesia. SWs are essential to neural plasticity and memory. However, much remains unknown about the mechanisms coordinating SW propagation at the macroscale. To assess SWs in the context of macroscale networks, we recorded cortical activity in awake and ketamine/xylazine-anesthetized mice using widefield optical imaging with fluorescent calcium indicator GCaMP6f. We demonstrate that unilateral somatosensory stimulation evokes bilateral waves that travel across the cortex with state-dependent trajectories. Under anesthesia, we observe that rhythmic stimuli elicit globally resonant, front-to-back propagating SWs. Finally, photothrombotic lesions of S1 show that somatosensory-evoked global SWs depend on bilateral recruitment of homotopic primary somatosensory cortices. Specifically, unilateral lesions of S1 disrupt somatosensory-evoked global SW initiation from either hemisphere, while spontaneous SWs are largely unchanged. These results show that evoked SWs may be triggered by bilateral activation of specific, homotopically connected cortical networks. © 2021 National Academy of Sciences. All rights reserved.

Author Keywords
Propagation;  Slow wave;  Somatosensory cortex

Funding details
National Science FoundationNSFDGE-1745038
National Institutes of HealthNIHF31NS103275, P01NS080675, P30NS098577, R01NS090874, R01NS099429, R37NS110699
American Heart AssociationAHA20PRE34990003

Document Type: Article
Publication Stage: Final
Source: Scopus

Focused ultrasound-mediated intranasal brain drug delivery technique (FUSIN)” (2021) MethodsX

Focused ultrasound-mediated intranasal brain drug delivery technique (FUSIN)
(2021) MethodsX, 8, art. no. 101266, . 

Ye, D.a , Chen, H.b c

a Department of Mechanical Engineering and Material Science, Washington University in St. Louis, Saint Louis, MO 63130, United States
b Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO 63130, United States
c Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO 63108, United States

Abstract
The blood-brain barrier (BBB) is the major obstacle for brain drug delivery and limits the treatment options for central nervous system diseases. To circumvent the BBB, we introduce focused ultrasound-mediated intranasal brain drug delivery (FUSIN). FUSIN utilizes the nasal route for direct nose-to-brain drug administration, bypassing the BBB and minimizing systemic exposure to the major organs, such as heart, lung, liver, and kidney [1]. It also uses transcranial ultrasound energy focused at a targeted brain region to induce microbubble cavitation, enhancing the transport of intranasally administered agents at the FUS-targeted brain location. FUSIN is unique because it can achieve noninvasive and localized brain drug delivery with minimized systemic toxicity to other major organs. The goal of this paper is to provide a detailed protocol for FUSIN delivery to the mouse brain. • FUSIN delivery utilizes the nose-to-brain pathway for brain drug delivery. • FUSIN utilizes FUS combined with microbubble to significantly enhance the delivery efficiency of intranasally administered drugs to the FUS targeted brain regions. • FUSIN achieves efficient brain delivery with minimized systemic exposure in the major organs. © 2021 The Authors

Author Keywords
Blood-brain barrier;  Brain drug delivery;  Focused ultrasound;  Focused ultrasound-mediated intranasal brain drug delivery technique (FUSIN);  Intranasal administration;  Microbubbles

Funding details
800CW-BSA
National Institutes of HealthNIHR01EB027223, R01EB030102, R01MH116981

Document Type: Article
Publication Stage: Final
Source: Scopus

MR Elastography demonstrates reduced white matter shear stiffness in early-onset hydrocephalus” (2021) NeuroImage: Clinical

MR Elastography demonstrates reduced white matter shear stiffness in early-onset hydrocephalus
(2021) NeuroImage: Clinical, 30, art. no. 102579, . 

Wagshul, M.E.a , McAllister, J.P.b , Limbrick, D.D., Jr.b c , Yang, S.a , Mowrey, W.d , Goodrich, J.T.e , Meiri, A.a , Morales, D.M.b , Kobets, A.e , Abbott, R.e

a Albert Einstein College of Medicine, Gruss MRRC, Departments of Radiology and Physiology & Biophysics, Bronx, NY, United States
b Saint Louis Children’s Hospital and the Department of Neurosurgery, Washington University School of Medicine, Saint Louis, MO, United States
c Department of Pediatrics, Washington University, School of Medicine, United States
d Albert Einstein College of Medicine, Department of Epidemiology and Population Health, Bronx, NY, United States
e Montefiore Medical Center, Department of Neurosurgery, Bronx, NY, United States

Abstract
Introduction: Hydrocephalus that develops early in life is often accompanied by developmental delays, headaches and other neurological deficits, which may be associated with changes in brain shear stiffness. However, noninvasive approaches to measuring stiffness are limited. Magnetic Resonance Elastography (MRE) of the brain is a relatively new noninvasive imaging method that provides quantitative measures of brain tissue stiffness. Herein, we aimed to use MRE to assess brain stiffness in hydrocephalus patients compared to healthy controls, and to assess its associations with ventricular size, as well as demographic, shunt-related and clinical outcome measures. Methods: MRE was collected at two imaging sites in 39 hydrocephalus patients and 33 healthy controls, along with demographic, shunt-related, and clinical outcome measures including headache and quality of life indices. Brain stiffness was quantified for whole brain, global white matter (WM), and lobar WM stiffness. Group differences in brain stiffness between patients and controls were compared using two-sample t-tests and multivariable linear regression to adjust for age, sex, and ventricular volume. Among patients, multivariable linear or logistic regression was used to assess which factors (age, sex, ventricular volume, age at first shunt, number of shunt revisions) were associated with brain stiffness and whether brain stiffness predicts clinical outcomes (quality of life, headache and depression). Results: Brain stiffness was significantly reduced in patients compared to controls, both unadjusted (p ≤ 0.002) and adjusted (p ≤ 0.03) for covariates. Among hydrocephalic patients, lower stiffness was associated with older age in temporal and parietal WM and whole brain (WB) (beta (SE): −7.6 (2.5), p = 0.004; −9.5 (2.2), p = 0.0002; −3.7 (1.8), p = 0.046), being female in global and frontal WM and WB (beta (SE): −75.6 (25.5), p = 0.01; −66.0 (32.4), p = 0.05; −73.2 (25.3), p = 0.01), larger ventricular volume in global, and occipital WM (beta (SE): −11.5 (3.4), p = 0.002; −18.9 (5.4), p = 0.0014). Lower brain stiffness also predicted worse quality of life and a higher likelihood of depression, controlling for all other factors. Conclusions: Brain stiffness is reduced in hydrocephalus patients compared to healthy controls, and is associated with clinically-relevant functional outcome measures. MRE may emerge as a clinically-relevant biomarker to assess the neuropathological effects of hydrocephalus and shunting, and may be useful in evaluating the effects of therapeutic alternatives, or as a supplement, of shunting. © 2021 The Authors

Author Keywords
MR Elastography;  Pediatric hydrocephalus;  Quality of life;  Shear stiffness;  Shunting;  White matter stiffness

Document Type: Article
Publication Stage: Final
Source: Scopus

Obesity and White Matter Neuroinflammation Related Edema in Alzheimer’s Disease Dementia Biomarker Negative Cognitively Normal Individuals” (2021) Journal of Alzheimer’s Disease

Obesity and White Matter Neuroinflammation Related Edema in Alzheimer’s Disease Dementia Biomarker Negative Cognitively Normal Individuals
(2021) Journal of Alzheimer’s Disease, 79 (4), pp. 1801-1811. 

Ly, M.a , Raji, C.A.b c , Yu, G.Z.a , Wang, Q.b , Wang, Y.b , Schindler, S.E.c , An, H.b , Samara, A.d , Eisenstein, S.A.b d , Hershey, T.b c d e , Smith, G.f , Klein, S.f , Liu, J.g , Xiong, C.g , Ances, B.M.c , Morris, J.C.c , Benzinger, T.L.S.b

a University of Pittsburgh Medical Scientist Training Program, Pittsburgh, PA, United States
b Mallinckrodt Institute of Radiology, Division of Neuroradiology, Washington University in St. Louis, St. Louis, MO, United States
c Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
d Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
e Department of Psychological Brain Sciences, Washington University School of Medicine, St. Louis, MO, United States
f Center for Human Nutrition, Washington University in St. Louis, St. Louis, MO, United States
g Department of Biostatistics, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Background: Obesity is related to quantitative neuroimaging abnormalities including reduced gray matter volumes and impaired white matter microstructural integrity, although the underlying mechanisms are not well understood. Objective: We assessed influence of obesity on neuroinflammation imaging that may mediate brain morphometric changes. Establishing the role of neuroinflammation in obesity will enhance understanding of this modifiable disorder as a risk factor for Alzheimer’s disease (AD) dementia. Methods: We analyzed brain MRIs from 104 cognitively normal participants (CDR=0) and biomarker negativity for CSF amyloid or tau. We classified body mass index (BMI) as normal (BMI <25, N=62) or overweight and obese (BMI ≥25, N=42). Blood pressure was measured. BMI and blood pressure classifications were related to neuroinflammation imaging (NII) derived edema fraction in 17 white matter tracts. This metric was also correlated to hippocampal volumes and CSF biomarkers of inflammation and neurodegeneration: YKL-40, SNAP25, VILIP, tau, and NFL. Results: Participants with BMI <25 had lower NII-derived edema fraction, with protective effects of normal blood pressure. Statistically significant white matter tracts included the internal capsule, external capsule, and corona radiata, FDR correc-ted for multiple comparisons to alpha=0.05. Higher NII-derived edema fractions in the internal capsule, corpus callosum, gyrus, and superior fronto-occipital fasciculus were related with smaller hippocampal volumes only in individuals with BMI ≥25. There were no statistically significant correlations between NII-derived edema fraction and CSF biomarkers. Conclusion: We demonstrate statistically significant relationships between neuroinflammation, elevated BMI, and hippocampal volume, raising implications for neuroinflammation mechanisms of obesity-related brain dysfunction in cognitively normal elderly. © 2021 – IOS Press. All rights reserved.

Author Keywords
Alzheimer’s disease;  neuroinflammation imaging;  obesity

Funding details
KL2 TR000450
National Institutes of HealthNIHP01AG003991, P01AG026276, P50AG005681
Radiological Society of North AmericaRSNA

Document Type: Article
Publication Stage: Final
Source: Scopus

Spatially constrained kinetic modeling with dual reference tissues improves 18F-flortaucipir PET in studies of Alzheimer disease” (2021) European Journal of Nuclear Medicine and Molecular Imaging

Spatially constrained kinetic modeling with dual reference tissues improves 18F-flortaucipir PET in studies of Alzheimer disease
(2021) European Journal of Nuclear Medicine and Molecular Imaging, . 

Zhou, Y.a , Flores, S.a , Mansor, S.a , Hornbeck, R.C.a , Tu, Z.a , Perlmutter, J.S.a b , Ances, B.c , Morris, J.C.b c , Gropler, R.J.a , Benzinger, T.L.S.a b c

a Mallinckrodt Institute of Radiology, Washington University School of Medicine, Campus Box 8225, 510 S. Kingshighway Blvd, St Louis, MO 63110, United States
b Departments of Neurology and Neuroscience, Programs of Physical Therapy and Occupational Therapy, Washington University School of Medicine, Saint Louis, MO, United States
c Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
Purpose: Recent studies have shown that standard compartmental models using plasma input or the cerebellum reference tissue input are generally not reliable for quantifying tau burden in dynamic 18F-flortaucipir PET studies of Alzheimer disease. So far, the optimal reference region for estimating 18F-flortaucipir delivery and specific tau binding has yet to be determined. The objective of the study is to improve 18F-flortaucipir brain tau PET quantification using a spatially constrained kinetic model with dual reference tissues. Methods: Participants were classified as either cognitively normal (CN) or cognitively impaired (CI) based on clinical assessment. T1-weighted structural MRI and 105-min dynamic 18F-flortaucipir PET scans were acquired for each participant. Using both a simplified reference tissue model (SRTM2) and Logan plot with either cerebellum gray matter or centrum semiovale (CS) white matter as the reference tissue, we estimated distribution volume ratios (DVRs) and the relative transport rate constant R1 for region of interest-based (ROI) and voxelwise-based analyses. Conventional linear regression (LR) and LR with spatially constrained (LRSC) parametric imaging algorithms were then evaluated. Noise-induced bias in the parametric images was compared to estimates from ROI time activity curve-based kinetic modeling. We finally evaluated standardized uptake value ratios at early phase (SUVREP, 0.7–2.9 min) and late phase (SUVRLP, 80–105 min) to approximate R1 and DVR, respectively. Results: The percent coefficients of variation of R1 and DVR estimates from SRTM2 with spatially constrained modeling were comparable to those from the Logan plot and SUVRs. The SRTM2 using CS reference tissue with LRSC reduced noise-induced underestimation in the LR generated DVR images to negligible levels (&lt; 1%). Inconsistent overestimation of DVR in the SUVRLP only occurred using the cerebellum reference tissue-based measurements. The CS reference tissue-based DVR and SUVRLP, and cerebellum-based SUVREP and R1 provided higher Cohen’s effect size d to detect increased tau deposition and reduced relative tracer transport rate in CI individuals. Conclusion: Using a spatially constrained kinetic model with dual reference tissues significantly improved quantification of relative perfusion and tau binding. Cerebellum and CS are the suggested reference tissues to estimate R1 and DVR, respectively, for dynamic 18F-flortaucipir PET studies. Cerebellum-based SUVREP and CS-based SUVRLP may be used to simplify 18F-flortaucipir PET study. © 2021, Springer-Verlag GmbH Germany, part of Springer Nature.

Author Keywords
18F-Flortaucipir PET;  Alzheimer disease;  Dual reference tissues;  Logan plot;  Spatially constrained kinetic modeling;  SRTM;  SUVR

Funding details
National Institutes of HealthNIH1RO1HL150891-01, 2P01AG003991-36, P01AG026276, P41EB025815, P50 AG05681, U01AG042791, U19 AG032438-08
Washington University School of Medicine in St. Louis

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

Miyoshi myopathy and limb girdle muscular dystrophy R2 are the same disease” (2021) Neuromuscular Disorders

Miyoshi myopathy and limb girdle muscular dystrophy R2 are the same disease
(2021) Neuromuscular Disorders, . 

Moore, U.a , Gordish, H.b c , Diaz-Manera, J.d e , James, M.K.a , Mayhew, A.G.a , Guglieri, M.a , Fernandez-Torron, R.a , Rufibach, L.E.f , Feng, J.b , Blamire, A.M.g , Carlier, P.G.h , Spuler, S.i , Day, J.W.j , Jones, K.J.k , Bharucha-Goebel, D.X.l m , Salort-Campana, E.n , Pestronk, A.o , Walter, M.C.p , Paradas, C.q , Stojkovic, T.r , Mori-Yoshimura, M.s , Bravver, E.t , Pegoraro, E.u , Lowes, L.P.v , Mendell, J.R.v , Bushby, K.a , Straub, V.a , Jain COS Consortiumw

a The John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Central Parkway, Newcastle upon Tyne, United Kingdom
b Center for Translational Science, Division of Biostatistics and Study Methodology, Children’s National Health SystemWashington, DC, United States
c Pediatrics, Epidemiology and Biostatistics, George Washington UniversityWashington, DC, United States
d Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Barcelona, Spain
e Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau
f The Jain Foundation, Seattle, Washington DC, United States
g Magnetic Resonance Centre, Translational and Clinical Research Institute, Newcastle University, United Kingdom
h AIM & CEA NMR Laboratory, Institute of Myology, Pitié-Salpêtrière University Hospital, Paris, 47-83, France
i Charite Muscle Research Unit, Experimental and Clinical Research Center, a Joint Cooperation of the Charité Medical Faculty and the Max Delbrück Center for Molecular Medicine, Berlin, Germany
j Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, United States
k The Children’s Hospital at Westmead, and The University of Sydney, Australia
l Department of Neurology Children’s National Health SystemWashington, DC, United States
m National Institutes of Health (NINDS), Bethesda, MD, United States
n Service des maladies neuromusculaire et de la SLA, Hôpital de La Timone, Marseille, France
o Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
p Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University of Munich, Germany
q Neuromuscular Unit, Department of Neurology, Hospital U. Virgen del Rocío/Instituto de Biomedicina de Sevilla, Sevilla, Spain
r Centre de référence des maladies neuromusculaires, Institut de Myologie, AP-HP, Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France
s Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan
t Neuroscience Institute, Carolinas Neuromuscular/ALS-MDA Center, Carolinas HealthCare System, Charlotte, NC, United States
u Department of Neuroscience, University of Padova, Italy
v The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States

Abstract
This study aims to determine clinically relevant phenotypic differences between the two most common phenotypic classifications in dysferlinopathy, limb girdle muscular dystrophy R2 (LGMDR2) and Miyoshi myopathy (MMD1). LGMDR2 and MMD1 are reported to involve different muscles, with LGMDR2 showing predominant limb girdle weakness and MMD1 showing predominant distal lower limb weakness. We used heatmaps, regression analysis and principle component analysis of functional and Magnetic Resonance Imaging data to perform a cross-sectional review of the pattern of muscle involvement in 168 patients from the Jain Foundation’s international Clinical Outcomes Study for Dysferlinopathy. We demonstrated that there is no clinically relevant difference in proximal vs distal involvement between diagnosis. There is a continuum of distal involvement at any given degree of proximal involvement and patients do not fall into discrete distally or proximally affected groups. There appeared to be geographical preference for a particular diagnosis, with MMD1 being more common in Japan and LGMDR2 in Europe and the USA. We conclude that the dysferlinopathies do not form two distinct phenotypic groups and therefore should not be split into separate cohorts of LGMDR2 and MM for the purposes of clinical management, enrolment in clinical trials or access to subsequent treatments. © 2021 The Authors

Author Keywords
[16] Clinical neurology examination;  [176] All neuromuscular disease;  [185] Muscle disease;  [21] Clinical trials methodology;  [54] Cohort study

Funding details
MR/S005021/1
Jain Foundation
Biogen
Medical Research CouncilMRC

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

Integrated molecular and clinical analysis of low-grade gliomas in children with neurofibromatosis type 1 (NF1)” (2021) Acta Neuropathologica

Integrated molecular and clinical analysis of low-grade gliomas in children with neurofibromatosis type 1 (NF1)
(2021) Acta Neuropathologica, . 

Fisher, M.J.a , Jones, D.T.W.b c , Li, Y.d , Guo, X.e , Sonawane, P.S.f , Waanders, A.J.a w , Phillips, J.J.g , Weiss, W.A.h , Resnick, A.C.f , Gosline, S.i x , Banerjee, J.i , Guinney, J.i , Gnekow, A.j , Kandels, D.j , Foreman, N.K.k , Korshunov, A.l , Ryzhova, M.m , Massimi, L.n ab , Gururangan, S.o , Kieran, M.W.p y , Wang, Z.q z , Fouladi, M.r aa , Sato, M.s , Øra, I.t , Holm, S.u , Markham, S.J.a , Beck, P.b c , Jäger, N.b c , Wittmann, A.b , Sommerkamp, A.C.b c , Sahm, F.l , Pfister, S.M.b c v , Gutmann, D.H.e

a Division of Oncology, The Children’s Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA, United States
b Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
c Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
d Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA, United States
e Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8111, St. Louis, MO 63110, United States
f Division of Neurosurgery, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
g Departments of Pathology, University of California, San Francisco, CA, United States
h Departments of Neurology, University of California, San Francisco, CA, United States
i Sage Bionetworks, Seattle, WA, United States
j Faculty of Medicine, University Augsburg, Augsburg, Germany
k University of Colorado, Denver, CO, United States
l Department of Neuropathology, Heidelberg University, Heidelberg, Germany
m Department of Neuropathology, NN Burdenko Neurosurgical Research Centre, Moscow, Russian Federation
n Fondazione Policlinico A. Gemelli, IRCCS, Rome, Italy
o Department of Neurosurgery, UF Health Shands Hospital, Gainesville, FL, United States
p Department of Pediatrics, Dana-Farber Cancer Institute, Boston, MA, United States
q Division of Hematology/Oncology, Children’s Hospital of Michigan, Detroit, MI, United States
r Division of Hematology/Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
s Division of Hematology/Oncology, University of Iowa Stead Family Children’s Hospital, Iowa City, IA, United States
t Lund University Cancer Center, Lund University, Lund, Sweden
u Karolinska University Hospital, Stockholm, Sweden
v Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany
w Division of Hematology/Oncology, Lurie Children’s Hospital of Chicago, Chicago, IL, United States
x Pacific Northwest National Laboratory, Seattle, WA, United States
y Bristol Myers Squibb, Lawrenceville, NJ, United States
z Division of Hematology and Oncology, Children’s Hospital of Richmond, Richmond, VA, United States
aa Division of Hematology and Oncology, Nationwide Children’s Hospital, Columbus, OH, United States
ab Pediatric Neurosurgery, A. Gemelli Hospital, Rome, Italy

Abstract
Low-grade gliomas (LGGs) are the most common childhood brain tumor in the general population and in individuals with the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome. Surgical biopsy is rarely performed prior to treatment in the setting of NF1, resulting in a paucity of tumor genomic information. To define the molecular landscape of NF1-associated LGGs (NF1-LGG), we integrated clinical data, histological diagnoses, and multi-level genetic/genomic analyses on 70 individuals from 25 centers worldwide. Whereas, most tumors harbored bi-allelic NF1 inactivation as the only genetic abnormality, 11% had additional mutations. Moreover, tumors classified as non-pilocytic astrocytoma based on DNA methylation analysis were significantly more likely to harbor these additional mutations. The most common secondary alteration was FGFR1 mutation, which conferred an additional growth advantage in multiple complementary experimental murine Nf1 models. Taken together, this comprehensive characterization has important implications for the management of children with NF1-LGG, distinct from their sporadic counterparts. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.

Author Keywords
FGFR1;  Methylation;  Neurofibromatosis;  Pediatric brain tumor;  Pilocytic astrocytoma

Funding details
Children’s Tumor FoundationCTF2015-18-004

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