Hope Center member publications

Li, F.^a , Jiang, H.^a , Shen, X.^a , Yang, W.^a , Guo, C.^a , Wang, Z.^a , Xiao, M.^a , Cui, L.^b , Luo, W.^b , Kim, B.S.^a c , Chen, Z.^a c d e , Huang, A.J.W.^f , Liu, Q.^a c f g

Sneezing reflex is mediated by a peptidergic pathway from nose to brainstem
(2021) Cell, 184 (14), pp. 3762-3773.e10. 

^a Department of Anesthesiology, Center for the Study of Itch and Sensory Disorders, and Washington University Pain Center, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
^c Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
^f Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, United States
^g Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Sneezing is a vital respiratory reflex frequently associated with allergic rhinitis and viral respiratory infections. However, its neural circuit remains largely unknown. A sneeze-evoking region was discovered in both cat and human brainstems, corresponding anatomically to the central recipient zone of nasal sensory neurons. Therefore, we hypothesized that a neuronal population postsynaptic to nasal sensory neurons mediates sneezing in this region. By screening major presynaptic neurotransmitters/neuropeptides released by nasal sensory neurons, we found that neuromedin B (NMB) peptide is essential for signaling sneezing. Ablation of NMB-sensitive postsynaptic neurons in the sneeze-evoking region or deficiency in NMB receptor abolished the sneezing reflex. Remarkably, NMB-sensitive neurons further project to the caudal ventral respiratory group (cVRG). Chemical activation of NMB-sensitive neurons elicits action potentials in cVRG neurons and leads to sneezing behavior. Our study delineates a peptidergic pathway mediating sneezing, providing molecular insights into the sneezing reflex arc. © 2021 Elsevier Inc.

Author Keywords
caudal ventral respiratory group;  nasal sensory neurons;  neuropeptide;  sneeze;  sneeze-evoking region

Funding details
National Institutes of HealthNIHR01AI125743, R01EY024704
National Institute of Arthritis and Musculoskeletal and Skin DiseasesNIAMSK08-AR065577, R01AR070116, R01AR077007
Doris Duke Charitable FoundationDDCF
Boehringer IngelheimBI
American Skin AssociationASA
Pfizer
AbbVie
Cidara Therapeutics
Kiniksa Pharmaceuticals

Document Type: Article
Publication Stage: Final
Source: Scopus

Mechanical and mechanothermal effects of focused ultrasound elicited distinct electromyographic responses in mice
(2021) Physics in Medicine and Biology, 66 (13), art. no. 135005, . 

Baek, H.^a , Yang, Y.^a , Pacia, C.P.^a , Xu, L.^a , Yue, Y.^a , Bruchas, M.R.^b , Chen, H.^a c

^a Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO 63130, United States
^b Department of Anesthesiology and Pain Medicine, Center for Neurobiology of Addiction, Pain and Emotion, University of Washington, Seattle, WA 98195, United States
^c Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO 63108, United States

Abstract
The objective of this study was to compare focused ultrasound (FUS) neuromodulation-induced motor responses under two physical mechanisms: mechanical and mechanothermal effects. Mice were divided into two groups. One group was subjected to short-duration FUS stimulation (0.3 s) that induced mechanical effects (mechanical group). The other group underwent long-duration FUS stimulation (15 s) that produced not only mechanical but also thermal effects (mechanothermal group). FUS was targeted at the deep cerebellar nucleus in the cerebellum to induce motor responses, which were evaluated by recording the evoked electromyographic (EMG) signals and tail movements. Brain tissue temperature rise associated with the FUS stimulation was quantified by noninvasive magnetic resonance thermometry in vivo. Temperature rise was negligible for the mechanical group (0.2 °C ± 0.1 °C) but did rise within the range of 0.6 °C ± 0.2 °C-3.3 °C ± 0.9 °C for the mechanothermal group. The elongated FUS beam also induced heating in the dorsal brain (below the top skull) and ventral brain (above the bottom skull) along the beam path for the mechanothermal group. Both mechanical and mechanothermal groups achieved successful FUS neuromodulation. EMG response latencies were within the range of 0.03-0.1 s at different intensity levels for the mechanical group. The mechanothermal effect of FUS could induce both short-latency EMG (0.2-1.4 s) and long-latency EMG (8.7-13.0 s) under the same intensity levels as the mechanical group. The different temporal dynamics of evoked EMG suggested that FUS-induced mechanical and mechanothermal effects could evoke different responses in the brain. © 2021 Institute of Physics and Engineering in Medicine.

Author Keywords
electromyography;  focused ultrasound;  motor response;  neuromodulation

Funding details
National Institutes of HealthNIHR01MH116981
National Institute of Biomedical Imaging and BioengineeringNIBIBR01EB027223, R01EB030102

Document Type: Article
Publication Stage: Final
Source: Scopus

Patient-derived iPSC-cerebral organoid modeling of the 17q11.2 microdeletion syndrome establishes CRLF3 as a critical regulator of neurogenesis
(2021) Cell Reports, 36 (1), art. no. 109315, . 

Wegscheid, M.L., Anastasaki, C., Hartigan, K.A., Cobb, O.M., Papke, J.B., Traber, J.N., Morris, S.M., Gutmann, D.H.

Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Neurodevelopmental disorders are often caused by chromosomal microdeletions comprising numerous contiguous genes. A subset of neurofibromatosis type 1 (NF1) patients with severe developmental delays and intellectual disability harbors such a microdeletion event on chromosome 17q11.2, involving the NF1 gene and flanking regions (NF1 total gene deletion [NF1-TGD]). Using patient-derived human induced pluripotent stem cell (hiPSC)-forebrain cerebral organoids (hCOs), we identify both neural stem cell (NSC) proliferation and neuronal maturation abnormalities in NF1-TGD hCOs. While increased NSC proliferation results from decreased NF1/RAS regulation, the neuronal differentiation, survival, and maturation defects are caused by reduced cytokine receptor-like factor 3 (CRLF3) expression and impaired RhoA signaling. Furthermore, we demonstrate a higher autistic trait burden in NF1 patients harboring a deleterious germline mutation in the CRLF3 gene (c.1166T>C, p.Leu389Pro). Collectively, these findings identify a causative gene within the NF1-TGD locus responsible for hCO neuronal abnormalities and autism in children with NF1. © 2021 The Author(s)

Author Keywords
autism;  brain development;  cerebral organoids;  CRLF3;  human induced pluripotent stem cells;  intellectual disability;  microdeletion;  neurofibromatosis type 1;  neurons;  RAS

Funding details
National Institutes of HealthNIH1-R35-NS07211-01
National Cancer InstituteNCIP30-CA091842
Children’s Tumor FoundationCTF2018-01-003

Document Type: Article
Publication Stage: Final
Source: Scopus

Image segmentation for neuroscience: Lymphatics
(2021) JPhys Photonics, 3 (3), art. no. e035004, . 

Tabassum, N.^a f , Wang, J.^a , Ferguson, M.^b , Herz, J.^c , Dong, M.^d , Louveau, A.^e , Kipnis, J.^c , Acton, S.T.^a

^a Department of Electrical and Computer Engineering, University of Virginia, Charlottesville, VA, United States
^b Department of Computer Science, University of Virginia, Charlottesville, VA, United States
^c Department of Pathology and Immunology, Washington University School of Medicine in St Louis, St Louis, MO, United States
^d Internal Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States
^e Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
^f Analytic Server R&D Testing, SAS Institute, Cary, NC 27513, United States

Abstract
A recent discovery in neuroscience prompts the need for innovation in image analysis. Neuroscientists have discovered the existence of meningeal lymphatic vessels in the brain and have shown their importance in preventing cognitive decline in mouse models of Alzheimer s disease. With age, lymphatic vessels narrow and poorly drain cerebrospinal fluid, leading to plaque accumulation, a marker for Alzheimer s disease. The detection of vessel boundaries and width are performed by hand in current practice and thereby suffer from high error rates and potential observer bias. The existing vessel segmentation methods are dependent on user-defined initialization, which is time-consuming and difficult to achieve in practice due to high amounts of background clutter and noise. This work proposes a level set segmentation method featuring hierarchical matting, LyMPhi, to predetermine foreground and background regions. The level set force field is modulated by the foreground information computed by matting, while also constraining the segmentation contour to be smooth. Segmentation output from this method has a higher overall Dice coefficient and boundary F1-score compared to that of competing algorithms. The algorithms are tested on real and synthetic data generated by our novel shape deformation based approach. LyMPhi is also shown to be more stable under different initial conditions as compared to existing level set segmentation methods. Finally, statistical analysis on manual segmentation is performed to prove the variation and disagreement between three annotators. © JPhys Complexity 2021. All rights reserved.

Author Keywords
data augmentation;  deformation transfer;  level-set segmentation;  manual segmentation;  meningeal lymphatics;  shape transform;  vessel segmentation

Funding details
University of VirginiaUV

Document Type: Article
Publication Stage: Final
Source: Scopus

Targeting the gut to treat multiple sclerosis
(2021) Journal of Clinical Investigation, 131 (13), art. no. e143774, . 

Ghezzi, L.^a b , Cantoni, C.^a , Pinget, G.V.^c , Zhou, Y.^d , Piccio, L.^a e f

^a Department of Neurology, School of Medicine, Washington University in St. Louis, St. Louis, MS, United States
^b University of Milan, Milan, Italy
^c Charles Perkins Centre, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
^d Department of Medicine, School of Medicine, UConn Health, Farmington, CT, United States
^e Brain and Mind Centre, School of Medical Sciences, University of Sydney, Sydney, NSW, Australia
^f Hope Center for Neurological Disorders, Department of Neurology, School of Medicine, Washington University in St. Louis, St. Louis, MS, United States

Abstract
The gut-brain axis (GBA) refers to the complex interactions between the gut microbiota and the nervous, immune, and endocrine systems, together linking brain and gut functions. Perturbations of the GBA have been reported in people with multiple sclerosis (pwMS), suggesting a possible role in disease pathogenesis and making it a potential therapeutic target. While research in the area is still in its infancy, a number of studies revealed that pwMS are more likely to exhibit altered microbiota, altered levels of short chain fatty acids and secondary bile products, and increased intestinal permeability. However, specific microbes and metabolites identified across studies and cohorts vary greatly. Small clinical and preclinical trials in pwMS and mouse models, in which microbial composition was manipulated through the use of antibiotics, fecal microbiota transplantation, and probiotic supplements, have provided promising outcomes in preventing CNS inflammation. However, results are not always consistent, and large-scale randomized controlled trials are lacking. Herein, we give an overview of how the GBA could contribute to MS pathogenesis, examine the different approaches tested to modulate the GBA, and discuss how they may impact neuroinflammation and demyelination in the CNS. © 2021, American Society for Clinical Investigation.

Funding details
2014/R/15
W81XWH-14-1-0156
National Institute of Neurological Disorders and StrokeNINDS
National Multiple Sclerosis SocietyFG-1907-34474, TA-1805-31003
Fondazione Italiana Sclerosi MultiplaFISM
Associazione Italiana Sclerosi MultiplaAISMFISM 2018/B/1

Document Type: Review
Publication Stage: Final
Source: Scopus

Maturation of Heterogeneity in Afferent Synapse Ultrastructure in the Mouse Cochlea
(2021) Frontiers in Synaptic Neuroscience, 13, art. no. 678575, . 

Payne, S.A.^a , Joens, M.S.^b c , Chung, H.^a d , Skigen, N.^d , Frank, A.^d , Gattani, S.^d , Vaughn, K.^d , Schwed, A.^e , Nester, M.^d , Bhattacharyya, A.^a d , Iyer, G.^d , Davis, B.^e , Carlquist, J.^a d , Patel, H.^d , Fitzpatrick, J.A.J.^b f g h , Rutherford, M.A.^a

^a Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO, United States
^b Center for Cellular Imaging, Washington University in St. Louis, St. Louis, MO, United States
^c TESCAN USA, Inc, Warrendale, PA, United States
^d Department of Biology, Washington University in St. Louis, St. Louis, MO, United States
^e Graduate Program in Audiology and Communications Sciences, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
^g Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, United States
^h Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Auditory nerve fibers (ANFs) innervating the same inner hair cell (IHC) may have identical frequency tuning but different sound response properties. In cat and guinea pig, ANF response properties correlate with afferent synapse morphology and position on the IHC, suggesting a causal structure-function relationship. In mice, this relationship has not been fully characterized. Here we measured the emergence of synaptic morphological heterogeneities during maturation of the C57BL/6J mouse cochlea by comparing postnatal day 17 (p17, ∼3 days after hearing onset) with p34, when the mouse cochlea is mature. Using serial block face scanning electron microscopy and three-dimensional reconstruction we measured the size, shape, vesicle content, and position of 70 ribbon synapses from the mid-cochlea. Several features matured over late postnatal development. From p17 to p34, presynaptic densities (PDs) and post-synaptic densities (PSDs) became smaller on average (PDs: 0.75 to 0.33; PSDs: 0.58 to 0.31 μm2) and less round as their short axes shortened predominantly on the modiolar side, from 770 to 360 nm. Membrane-associated synaptic vesicles decreased in number from 53 to 30 per synapse from p17 to p34. Anatomical coupling, measured as PSD to ribbon distance, tightened predominantly on the pillar side. Ribbons became less spherical as long-axes lengthened only on the modiolar side of the IHC, from 372 to 541 nm. A decreasing gradient of synaptic ribbon size along the modiolar-pillar axis was detected only at p34 after aligning synapses of adjacent IHCs to a common reference frame (median volumes in nm3 × 106: modiolar 4.87; pillar 2.38). The number of ribbon-associated synaptic vesicles scaled with ribbon size (range 67 to 346 per synapse at p34), thus acquiring a modiolar-pillar gradient at p34, but overall medians were similar at p17 (120) and p34 (127), like ribbon surface area (0.36 vs. 0.34 μm2). PD and PSD morphologies were tightly correlated to each other at individual synapses, more so at p34 than p17, but not to ribbon morphology. These observations suggest that PDs and PSDs mature according to different cues than ribbons, and that ribbon size may be more influenced by cues from the IHC than the surrounding tissue. © Copyright © 2021 Payne, Joens, Chung, Skigen, Frank, Gattani, Vaughn, Schwed, Nester, Bhattacharyya, Iyer, Davis, Carlquist, Patel, Fitzpatrick and Rutherford.

Author Keywords
developmental maturation;  FIB-SEM;  modiolar;  pillar;  postsynaptic density;  presynaptic density;  ribbon synapse ultrastructure;  synaptic vesicles

Funding details
S10OD021629
CDI-CORE-2015-505
National Institutes of HealthNIH
National Institute on Deafness and Other Communication DisordersNIDCDR01DC014712
Foundation for Barnes-Jewish Hospital
Washington University School of Medicine in St. Louis
Center for Cellular Imaging, Washington UniversityWUCCI

Document Type: Article
Publication Stage: Final
Source: Scopus

Group characterization of impact-induced, in vivo human brain kinematics
(2021) Journal of the Royal Society, Interface, 18 (179), p. 20210251. 

Gomez, A.D.^a , Bayly, P.V.^b , Butman, J.A.^c , Pham, D.L.^d , Prince, J.L.^e , Knutsen, A.K.^d

^a School of Medicine, Department of Neurology, Johns Hopkins University, 200 Carnegie Hall, MD, 600 North Wolfe Street, Baltimore, United States
^b Department of Mechanical Engineering and Materials Science, Washington University in St Louis, MI, 1 Brookings Drive, Box 1185, Saint Louis, United States
^c Clinical Center, National Institutes of Health, MD, Bethesda, United States
^d Center for Neuroscience and Regenerative Medicine, Henry M Jackson Foundation for the Advancement of Military Medicine Inc, MD, Bethesda, United States
^e Department of Electrical and Computer Engineering, Johns Hopkins University, MD, Baltimore, United States

Abstract
Brain movement during an impact can elicit a traumatic brain injury, but tissue kinematics vary from person to person and knowledge regarding this variability is limited. This study examines spatio-temporal brain-skull displacement and brain tissue deformation across groups of subjects during a mild impact in vivo. The heads of two groups of participants were imaged while subjected to a mild (less than 350 rad s-2) impact during neck extension (NE, n = 10) and neck rotation (NR, n = 9). A kinematic atlas of displacement and strain fields averaged across all participants was constructed and compared against individual participant data. The atlas-derived mean displacement magnitude was 0.26 ± 0.13 mm for NE and 0.40 ± 0.26 mm for NR, which is comparable to the displacement magnitudes from individual participants. The strain tensor from the atlas displacement field exhibited maximum shear strain (MSS) of 0.011 ± 0.006 for NE and 0.017 ± 0.009 for NR and was lower than the individual MSS averaged across participants. The atlas illustrates common patterns, containing some blurring but visible relationships between anatomy and kinematics. Conversely, the direction of the impact, brain size, and fluid motion appear to underlie kinematic variability. These findings demonstrate the biomechanical roles of key anatomical features and illustrate common features of brain response for model evaluation.

Author Keywords
dynamic magnetic resonance imaging;  finite strain;  head impact;  traumatic brain injury

Document Type: Article
Publication Stage: Final
Source: Scopus

Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations
(2021) Genetics in Medicine, . 

Rodan, L.H.^a b , Spillmann, R.C.^c , Kurata, H.T.^d , Lamothe, S.M.^d , Maghera, J.^d , Jamra, R.A.^e , Alkelai, A.^f , Antonarakis, S.E.^g , Atallah, I.^h , Bar-Yosef, O.^i j , Bilan, F.^k , Bjorgo, K.^l , Blanc, X.^g , Van Bogaert, P.^m , Bolkier, Y.^j n , Burrage, L.C.^o , Christ, B.U.^p , Granadillo, J.L.^q , Dickson, P.^q , Donald, K.A.^p , Dubourg, C.^r s , Eliyahu, A.^j t u , Emrick, L.^o , Engleman, K.^v , Gonfiantini, M.V.^w , Good, J.-M.^x , Kalser, J.^x , Kloeckner, C.^e , Lachmeijer, G.^y , Macchiaiolo, M.^w , Nicita, F.^z , Odent, S.^aa , O’Heir, E.^a ab , Ortiz-Gonzalez, X.^ac , Pacio-Miguez, M.^ad , Palomares-Bralo, M.^ad , Pena, L.^ae af , Platzer, K.^e , Quinodoz, M.^ag ah , Ranza, E.^g , Rosenfeld, J.A.^o , Roulet-Perez, E.^x , Santani, A.^ai aj , Santos-Simarro, F.^ad , Pode-Shakked, B.^j ak , Skraban, C.^aj al , Slaugh, R.^q , Superti-Furga, A.^x , Thiffault, I.^v , van Jaabrsveld, R.H.^y , Vincent, M.^am , Wang, H.-G.^an , Zacher, P.^ao , Alejandro, M.E.^at , Azamian, M.S.^at , Bacino, C.A.^at , Balasubramanyam, A.^at , Burrage, L.C.^at , Chao, H.-T.^at , Clark, G.D.^at , Craigen, W.J.^at , Dai, H.^at , Dhar, S.U.^at , Emrick, L.T.^at , Goldman, A.M.^at , Hanchard, N.A.^at , Jamal, F.^at , Karaviti, L.^at , Lalani, S.R.^at , Lee, B.H.^at , Lewis, R.A.^at , Marom, R.^at , Moretti, P.M.^at , Murdock, D.R.^at , Nicholas, S.K.^at , Orengo, J.P.^at , Posey, J.E.^at , Potocki, L.^at , Rosenfeld, J.A.^at , Samson, S.L.^at , Scott, D.A.^at , Tran, A.A.^at , Vogel, T.P.^at , Wangler, M.F.^au , Yamamoto, S.^au , Eng, C.M.^av , Liu, P.^av , Ward, P.A.^av , Behrens, E.^aw , Deardorff, M.^aw , Falk, M.^aw , Hassey, K.^aw , Sullivan, K.^aw , Vanderver, A.^aw , Goldstein, D.B.^ax , Cope, H.^ay , McConkie-Rosell, A.^ay , Schoch, K.^ay , Shashi, V.^ay , Smith, E.C.^ay , Spillmann, R.C.^ay , Sullivan, J.A.^ay , Tan, Q.K.-G.^ay , Walley, N.M.^ay , Agrawal, P.B.^az , Beggs, A.H.^az , Berry, G.T.^az , Briere, L.C.^az , Cobban, L.A.^az , Coggins, M.^az , Cooper, C.M.^az , Fieg, E.L.^az , High, F.^az , Holm, I.A.^az , Korrick, S.^az , Krier, J.B.^az , Lincoln, S.A.^az , Loscalzo, J.^az , Maas, R.L.^az , MacRae, C.A.^az , Pallais, J.C.^az , Rao, D.A.^az , Rodan, L.H.^az , Silverman, E.K.^az , Stoler, J.M.^az , Sweetser, D.A.^az , Walker, M.^az , Walsh, C.A.^az , Esteves, C.^ba , Kelley, E.G.^ba , Kohane, I.S.^ba , LeBlanc, K.^ba , McCray, A.T.^ba , Nagy, A.^ba , Dasari, S.^bb , Lanpher, B.C.^bb , Lanza, I.R.^bb , Morava, E.^bb , Oglesbee, D.^bb , Bademci, G.^bc , Barbouth, D.^bc , Bivona, S.^bc , Carrasquillo, O.^bc , Chang, T.C.P.^bc , Forghani, I.^bc , Grajewski, A.^bc , Isasi, R.^bc , Lam, B.^bc , Levitt, R.^bc , Liu, X.Z.^bc , McCauley, J.^bc , Sacco, R.^bc , Saporta, M.^bc , Schaechter, J.^bc , Tekin, M.^bc , Telischi, F.^bc , Thorson, W.^bc , Zuchner, S.^bc , Colley, H.A.^bd , Dayal, J.G.^bd , Eckstein, D.J.^bd , Findley, L.C.^bd , Krasnewich, D.M.^bd , Mamounas, L.A.^bd , Manolio, T.A.^bd , Mulvihill, J.J.^bd , LaMoure, G.L.^bd , Goldrich, M.P.^bd , Urv, T.K.^bd , Doss, A.L.^bd , Acosta, M.T.^be , Bonnenmann, C.^be , D’Souza, P.^be , Draper, D.D.^be , Ferreira, C.^be , Godfrey, R.A.^be , Groden, C.A.^be , Macnamara, E.F.^be , Maduro, V.V.^be , Markello, T.C.^be , Nath, A.^be , Novacic, D.^be , Pusey, B.N.^be , Toro, C.^be , Wahl, C.E.^be , Baker, E.^bf , Burke, E.A.^bg , Adams, D.R.^bg , Gahl, W.A.^bg , Malicdan, M.C.V.^bg , Tifft, C.J.^bg , Wolfe, L.A.^bg , Yang, J.^bg , Power, B.^bg , Gochuico, B.^bg , Huryn, L.^bg , Latham, L.^bg , Davis, J.^bg , Mosbrook-Davis, D.^bg , Rossignol, F.^bg , Ben Solomon^bg , MacDowall, J.^bg , Thurm, A.^bg , Zein, W.^bg , Yousef, M.^bg , Adam, M.^bh , Amendola, L.^bh , Bamshad, M.^bh , Beck, A.^bh , Bennett, J.^bh , Berg-Rood, B.^bh , Blue, E.^bh , Boyd, B.^bh , Byers, P.^bh , Chanprasert, S.^bh , Cunningham, M.^bh , Dipple, K.^bh , Doherty, D.^bh , Earl, D.^bh , Glass, I.^bh , Golden-Grant, K.^bh , Hahn, S.^bh , Hing, A.^bh , Hisama, F.M.^bh , Horike-Pyne, M.^bh , Jarvik, G.P.^bh , Jarvik, J.^bh , Jayadev, S.^bh , Lam, C.^bh , Maravilla, K.^bh , Mefford, H.^bh , Merritt, J.L.^bh , Mirzaa, G.^bh , Nickerson, D.^bh , Raskind, W.^bh , Rosenwasser, N.^bh , Scott, C.R.^bh , Sun, A.^bh , Sybert, V.^bh , Wallace, S.^bh , Wener, M.^bh , Wenger, T.^bh , Ashley, E.A.^bi , Bejerano, G.^bi , Bernstein, J.A.^bi , Bonner, D.^bi , Coakley, T.R.^bi , Fernandez, L.^bi , Fisher, P.G.^bi , Fresard, L.^bi , Hom, J.^bi , Huang, Y.^bi , Kohler, J.N.^bi , Kravets, E.^bi , Majcherska, M.M.^bi , Martin, B.A.^bi , Marwaha, S.^bi , McCormack, C.E.^bi , Raja, A.N.^bi , Reuter, C.M.^bi , Ruzhnikov, M.^bi , Sampson, J.B.^bi , Smith, K.S.^bi , Sutton, S.^bi , Tabor, H.K.^bi , Tucker, B.M.^bi , Wheeler, M.T.^bi , Zastrow, D.B.^bi , Zhao, C.^bi , Byrd, W.E.^bj , Crouse, A.B.^bj , Might, M.^bj , Nakano-Okuno, M.^bj , Whitlock, J.^bj , Brown, G.^bk , Butte, M.J.^bk , Dell’Angelica, E.C.^bk , Dorrani, N.^bk , Douine, E.D.^bk , Fogel, B.L.^bk , Gutierrez, I.^bk , Huang, A.^bk , Krakow, D.^bk , Lee, H.^bk , Loo, S.K.^bk , Mak, B.C.^bk , Martin, M.G.^bk , Martínez-Agosto, J.A.^bk , McGee, E.^bk , Nelson, S.F.^bk , Nieves-Rodriguez, S.^bk , Palmer, C.G.S.^bk , Papp, J.C.^bk , Parker, N.H.^bk , Renteria, G.^bk , Signer, R.H.^bk , Sinsheimer, J.S.^bk , Wan, J.^bk , Wang, L.-K.^bk , Perry, K.W.^bk , Woods, J.D.^bk , Alvey, J.^bl , Andrews, A.^bl , Bale, J.^bl , Bohnsack, J.^bl , Botto, L.^bl , Carey, J.^bl , Pace, L.^bl , Longo, N.^bl , Marth, G.^bl , Moretti, P.^bl , Quinlan, A.^bl , Velinder, M.^bl , Viskochil, D.^bl , Bayrak-Toydemir, P.^bm , Mao, R.^bm , Westerfield, M.^bn , Bican, A.^bo , Brokamp, E.^bo , Duncan, L.^bo , Hamid, R.^bo , Kennedy, J.^bo , Kozuira, M.^bo , Newman, J.H.^bo , PhillipsIII, J.A.^bo , Rives, L.^bo , Robertson, A.K.^bo , Solem, E.^bo , Cogan, J.D.^bo , Cole, F.S.^bp , Hayes, N.^bp , Kiley, D.^bp , Sisco, K.^bp , Wambach, J.^bp , Wegner, D.^bp , Baldridge, D.^bp , Pak, S.^bp , Schedl, T.^bp , Shin, J.^bp , Solnica-Krezel, L.^bp , Rush, E.^ap aq ar , Pitt, G.^an , Au, P.Y.B.^as , Shashi, V.^c , Undiagnosed Diseases Network^bq

^a Division of Genetics and Genomics, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, United States
^b Department of Neurology, Boston Children’s Hospital, Boston, MA, United States
^c Division of Medical Genetics, Department of Pediatrics, Duke Health, Durham, NC, United States
^d Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
^e Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
^f Institute for Genomic Medicine, Columbia University Medical Center, New York, NY, United States
^g Medigenome, Swiss Institute of Genomic Medicine, Geneva, Switzerland
^h Division of Genetic Medicine, Lausanne University Hospital, Lausanne, Switzerland
ⁱ Pediatric Neurology Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel-Hahsomer, Israel
^j Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
^k CHU de Poitiers, Service de Génétique, EA3808 NEUVACOD, Poitiers, France
^l Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
^m CHU d’Angers, Service de Pédiatrie, EA3808 NEUVACOD, Angers, France
ⁿ Pediatric Cardiology Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel-Hahsomer, Israel
^o Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, United States
^p Department of Paediatrics and Child Health, Red Cross War Memorial Children’s Hospital, University of Cape Town, Cape Town, SA, South Africa
^q Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^r Service de Génétique Moléculaire et Génomique, CHU, Rennes, France
^s University of Rennes, CNRS, IGDR, UMR 6290, Rennes, France
^t The Danek Gertner Insitute of Human Genetics, Sheba Medical Center, Tel-Hahsomer, Israel
^u Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel-Hahsomer, Israel
^v Center for Pediatric Genomic Medicine, Children’s Mercy Hospital, Kansas City, MO, United States
^w Rare Diseases and Medical Genetic Unit, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
^x Pediatric Neurology, Lausanne University Hospital, Lausanne, Switzerland
^y Department of Genetics, University Medical Center Utrecht, Utrecht, Netherlands
^z Unit of Neuromuscular and Neurodegenerative Diseases, Department of Neurosciences and Neurorehabilitation, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
^aa Service de Génétique Clinique, Centre de référence “Maladies Rares” Anomalies du développement CLAD-Ouest, Hôpital SUD, Échirolles, France
^ab Center for Mendelian Genomics and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, United States
^ac Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^ad Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz, IdiPAZ, CIBERER, ISCIII, Madrid, Spain
^ae Cincinnati Children’s Hospital and Medical Center Cincinnati, Cincinnati, OH, United States
^af University of Cincinnati College of Medicine Cincinnati, Cincinnati, OH, United States
^ag Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland
^ah Department of Ophthalmology, University of Basel, Basel, Switzerland
^ai Division of Genomic Diagnostics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^aj Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
^ak Institute of Rare Diseases, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel-Hahsomer, Israel
^al Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^am Service de Génétique Médicale, CHU Nantes, France; Inserm, CNRS, Univ Nantes, l’institut du thorax, Nantes, France
^an Cardiovascular Research Institute, Weill Cornell Medicine, New York, NY, United States
^ao The Saxon Epilepsy Center Kleinwachau, Radeberg, Germany
^ap The Children’s Mercy Hospital, Kansas City, MO, United States
^aq Department of Pediatrics University of Missouri—Kansas City, Kansas City, MO, United States
^ar Department of Internal Medicine, University of Kansas Medical Center, Kansas City, MO, United States
^as Alberta Children’s Hospital Research Institute, Department of Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
^at BCM Clinical, Houston, TX, United States
^au BCM MOSC, Houston, TX, United States
^av BCM Sequencing, Houston, TX, United States
^aw CHOP, Philadelphia, PA, United States
^ax Columbia University, New York, NY, United States
^ay Duke University, Durham, NC, United States
^az Harvard University, Boston, MA, United States
^ba Harvard CC, Boston, MA, United States
^bb Mayo Clinic, Rochester, MN, United States
^bc Miami, Miami, FL, United States
^bd NIH, Bethesda, MD, United States
^be NIH UDP, Bethesda, MD, United States
^bf NIH UDP, DRM, Bethesda, MD, United States
^bg NIH UDP, NHGRI, Bethesda, MD, United States
^bh PNW, Seattle, WA, United States
^bi Stanford, Stanford, CA, United States
^bj UAB CC, Birmingham, AL, United States
^bk UCLA, Los Angeles, CA, United States
^bl University of Utah, Salt Lake City, UT, United States
^bm University of Utah/ARUP, Salt Lake City, UT, United States
^bn UO MOSC, Eugene, OR, United States
^bo Vanderbilt, Nashville, TN, United States
^bp Washington University Clinical, St. Louis, MO, United States

Abstract
Purpose: CACNA1C encodes the alpha-1-subunit of a voltage-dependent L-type calcium channel expressed in human heart and brain. Heterozygous variants in CACNA1C have previously been reported in association with Timothy syndrome and long QT syndrome. Several case reports have suggested that CACNA1C variation may also be associated with a primarily neurological phenotype. Methods: We describe 25 individuals from 22 families with heterozygous variants in CACNA1C, who present with predominantly neurological manifestations. Results: Fourteen individuals have de novo, nontruncating variants and present variably with developmental delays, intellectual disability, autism, hypotonia, ataxia, and epilepsy. Functional studies of a subgroup of missense variants via patch clamp experiments demonstrated differential effects on channel function in vitro, including loss of function (p.Leu1408Val), neutral effect (p.Leu614Arg), and gain of function (p.Leu657Phe, p.Leu614Pro). The remaining 11 individuals from eight families have truncating variants in CACNA1C. The majority of these individuals have expressive language deficits, and half have autism. Conclusion: We expand the phenotype associated with CACNA1C variants to include neurodevelopmental abnormalities and epilepsy, in the absence of classic features of Timothy syndrome or long QT syndrome. © 2021, The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.

Funding details
B2017/BMD-3721
U01HG007709
National Institutes of HealthNIH
National Human Genome Research InstituteNHGRIR01 HG009141, UM1 HG008900
Duke University1RO1HD090132-01A1
Cornell UniversityCU
Baylor College of MedicineU01HG007672
Rare Disease FoundationRDF
Canadian Institutes of Health ResearchCIHRMOP-97988
University of AlbertaUofA

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

A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease
(2021) Nature Medicine, .

Salloway, S.^a , Farlow, M.^b , McDade, E.^c , Clifford, D.B.^c , Wang, G.^c , Llibre-Guerra, J.J.^c , Hitchcock, J.M.^d , Mills, S.L.^c , Santacruz, A.M.^c , Aschenbrenner, A.J.^c , Hassenstab, J.^c , Benzinger, T.L.S.^c , Gordon, B.A.^c , Fagan, A.M.^c , Coalier, K.A.^c , Cruchaga, C.^c , Goate, A.A.^e , Perrin, R.J.^c , Xiong, C.^c , Li, Y.^c , Morris, J.C.^c , Snider, B.J.^c , Mummery, C.^f , Surti, G.M.^a , Hannequin, D.^g , Wallon, D.^g , Berman, S.B.^h , Lah, J.J.ⁱ , Jimenez-Velazquez, I.Z.^j , Roberson, E.D.^k , van Dyck, C.H.^l , Honig, L.S.^m , Sánchez-Valle, R.ⁿ , Brooks, W.S.^o , Gauthier, S.^p , Galasko, D.R.^q , Masters, C.L.^r , Brosch, J.R.^b , Hsiung, G.-Y.R.^s , Jayadev, S.^t , Formaglio, M.^u , Masellis, M.^v , Clarnette, R.^w , Pariente, J.^x , Dubois, B.^y , Pasquier, F.^z , Jack, C.R., Jr.^aa , Koeppe, R.^ab , Snyder, P.J.^ac , Aisen, P.S.^ad , Thomas, R.G.^q , Berry, S.M.^ae , Wendelberger, B.A.^ae , Andersen, S.W.^af , Holdridge, K.C.^af , Mintun, M.A.^af , Yaari, R.^af , Sims, J.R.^af , Baudler, M.^ag , Delmar, P.^ag , Doody, R.S.^ag , Fontoura, P.^ag , Giacobino, C.^ag , Kerchner, G.A.^ag , Bateman, R.J.^c , Formaglio, M.^u , Mills, S.L.^c , Pariente, J.^x , van Dyck, C.H.^l , the Dominantly Inherited Alzheimer Network-Trials Unit^ah 

^a Warren Alpert Medical School of Brown University, Providence, RI, United States
^b Indiana University School of Medicine, Indianapolis, IN, United States
^c Washington University School of Medicine, St. Louis, MO, United States
^d Hitchcock Regulatory Consulting, Inc, Fishers, IN, United States
^e Icahn School of Medicine at Mount Sinai, New York, NY, United States
^f University College London, London, United Kingdom
^g Centre Hospitalier Universitaire de Rouen, Rouen, France
^h University of Pittsburgh Medical Center, Pittsburgh, PA, United States
ⁱ Emory University Medical Center, Atlanta, GA, United States
^j University of Puerto Rico School of Medicine, San Juan, Puerto Rico
^k University of Alabama at Birmingham School of Medicine, Birmingham, AL, United States
^l Yale University School of Medicine, New Haven, CT, United States
^m Columbia University Medical Center, New York, NY, United States
ⁿ Hospital Clínic i Provincial de Barcelona, August Pi i Sunyer Biomedical Research Institute-Universitat de Barcelona, Barcelona, Spain
^o Neuroscience Research Australia, University of New South Wales Medicine, Randwick, NSW, Australia
^p McGill Center for Studies in Aging, McGill University, Montreal, QC, Canada
^q University of California San Diego, San Diego, CA, United States
^r University of Melbourne, Melbourne, VIC, Australia
^s University of British Columbia, Vancouver, BC, Canada
^t University of Washington School of Medicine, Seattle, WA, United States
^u Hospices Civils de Lyon, Lyons, France
^v Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada
^w Australian Alzheimer’s Research Foundation, University of Western Australia, Perth, WA, Australia
^x Centre Hospitalier Universitaire de Toulouse, Toulouse, France
^y Neurological Institute, Salpetriere University Hospital, Paris, France
^z Centre Hospitalier Régional Universitaire de Lille, Lille, France
^aa Mayo Clinic, Rochester, MN, United States
^ab University of Michigan, Ann Arbor, MI, United States
^ac University of Rhode Island, Kingston, RI, United States
^ad Keck School of Medicine, University of Southern California, San Diego, CA, United States
^ae Berry Consultants, LLC, Austin, TX, United States
^af Eli Lilly and Company, Indianapolis, IN, United States
^ag F. Hoffmann-La Roche Ltd, Basel, Switzerland

Abstract
Dominantly inherited Alzheimer’s disease (DIAD) causes predictable biological changes decades before the onset of clinical symptoms, enabling testing of interventions in the asymptomatic and symptomatic stages to delay or slow disease progression. We conducted a randomized, placebo-controlled, multi-arm trial of gantenerumab or solanezumab in participants with DIAD across asymptomatic and symptomatic disease stages. Mutation carriers were assigned 3:1 to either drug or placebo and received treatment for 4–7 years. The primary outcome was a cognitive end point; secondary outcomes included clinical, cognitive, imaging and fluid biomarker measures. Fifty-two participants carrying a mutation were assigned to receive gantenerumab, 52 solanezumab and 40 placebo. Both drugs engaged their Aβ targets but neither demonstrated a beneficial effect on cognitive measures compared to controls. The solanezumab-treated group showed a greater cognitive decline on some measures and did not show benefits on downstream biomarkers. Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid total tau, and phospho-tau181 and attenuated increases of neurofilament light chain. Amyloid-related imaging abnormalities edema was observed in 19.2% (3 out of 11 were mildly symptomatic) of the gantenerumab group, 2.5% of the placebo group and 0% of the solanezumab group. Gantenerumab and solanezumab did not slow cognitive decline in symptomatic DIAD. The asymptomatic groups showed no cognitive decline; symptomatic participants had declined before reaching the target doses. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

Funding details
National Institutes of HealthNIHU01AG042791S1
Foundation for the National Institutes of HealthFNIHR01AG046179, R01AG053267S1
National Institute of Mental HealthNIMH
National Institute on AgingNIA
National Institute of Allergy and Infectious DiseasesNIAID
National Institute of Neurological Disorders and StrokeNINDS
Mayo Clinic
Alzheimer’s AssociationAA
Eli Lilly and Company
Roche
Biogen
National Center for Advancing Translational SciencesNCATS
AbbVie
F. Hoffmann-La Roche
Janssen Pharmaceuticals
Japan Agency for Medical Research and DevelopmentAMED
Avid RadiopharmaceuticalsP01AG003991, P01AG026276, P30 AG066444, U19 AG024904, U19 AG032438
GHR FoundationGHR
Canadian Institutes of Health ResearchCIHR
Alzheimer Society
Korea Health Industry Development InstituteKHIDI
Eisai
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE

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

Longitudinal CSF Iron Pathway Proteins in Posthemorrhagic Hydrocephalus: Associations with Ventricle Size and Neurodevelopmental Outcomes
(2021) Annals of Neurology, . 

Strahle, J.M.^a , Mahaney, K.B.^b , Morales, D.M.^a , Buddhala, C.^a , Shannon, C.N.^c , Wellons, J.C., III^c , Kulkarni, A.V.^d , Jensen, H.^e , Reeder, R.W.^e , Holubkov, R.^e , Riva-Cambrin, J.K.^f , Whitehead, W.E.^g , Rozzelle, C.J.^h , Tamber, M.ⁱ , Pollack, I.F.^j , Naftel, R.P.^c , Kestle, J.R.W.^k , Limbrick, D.D., Jr.^a , for the Hydrocephalus Clinical Research Network^l

^a Department of Neurosurgery, Washington University St. Louis, St. Louis, MO, United States
^b Department of Neurosurgery, Stanford University, Palo Alto, CA, United States
^c Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, TN, United States
^d Department of Neurosurgery, University of Toronto, Toronto, ON, Canada
^e Data Coordinating Center, University of Utah, Salt Lake City, UT, United States
^f Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada
^g Department of Neurosurgery, Baylor College of Medicine, Houston, TX, United States
^h Department of Neurosurgery, University of Alabama – Birmingham, Birmingham, AL, United States
ⁱ Department of Surgery, University of British Columbia, Vancouver, BC, Canada
^j Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
^k Department of Neurosurgery, University of Utah, Salt Lake City, UT, United States

Abstract
Objective: Iron has been implicated in the pathogenesis of brain injury and hydrocephalus after preterm germinal matrix hemorrhage-intraventricular hemorrhage, however, it is unknown how external or endogenous intraventricular clearance of iron pathway proteins affect the outcome in this group. Methods: This prospective multicenter cohort included patients with posthemorrhagic hydrocephalus (PHH) who underwent (1) temporary and permanent cerebrospinal fluid (CSF) diversion and (2) Bayley Scales of Infant Development-III testing around 2 years of age. CSF proteins in the iron handling pathway were analyzed longitudinally and compared to ventricle size and neurodevelopmental outcomes. Results: Thirty-seven patients met inclusion criteria with a median estimated gestational age at birth of 25 weeks; 65% were boys. Ventricular CSF levels of hemoglobin, iron, total bilirubin, and ferritin decreased between temporary and permanent CSF diversion with no change in CSF levels of ceruloplasmin, transferrin, haptoglobin, and hepcidin. There was an increase in CSF hemopexin during this interval. Larger ventricle size at permanent CSF diversion was associated with elevated CSF ferritin (p = 0.015) and decreased CSF hemopexin (p = 0.007). CSF levels of proteins at temporary CSF diversion were not associated with outcome, however, higher CSF transferrin at permanent CSF diversion was associated with improved cognitive outcome (p = 0.015). Importantly, longitudinal change in CSF iron pathway proteins, ferritin (decrease), and transferrin (increase) were associated with improved cognitive (p = 0.04) and motor (p = 0.03) scores and improved cognitive (p = 0.04), language (p = 0.035), and motor (p = 0.008) scores, respectively. Interpretation: Longitudinal changes in CSF transferrin (increase) and ferritin (decrease) are associated with improved neurodevelopmental outcomes in neonatal PHH, with implications for understanding the pathogenesis of poor outcomes in PHH. ANN NEUROL 2021. © 2021 American Neurological Association.

Funding details
National Institutes of HealthNIHK23 NS075151‐01A1, R01 NS110793
National Institute of Neurological Disorders and StrokeNINDS1RC1NS068943‐01, 1U01NS107486‐01A1, CER‐1403‐13857
Gerber Foundation1692–3638
Hydrocephalus AssociationHA

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