List of publications for October 3, 2022
Regulation of human cortical interneuron development by the chromatin remodeling protein CHD2
(2022) Scientific Reports, 12 (1), art. no. 15636, .
Lewis, E.M.A., Chapman, G., Kaushik, K., Determan, J., Antony, I., Meganathan, K., Narasimhan, M., Gontarz, P., Zhang, B., Kroll, K.L.
Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO 63110, United States
Abstract
Mutations in the chromodomain helicase DNA binding protein 2 (CHD2) gene are associated with neurodevelopmental disorders. However, mechanisms by which CHD2 regulates human brain development remain largely uncharacterized. Here, we used a human embryonic stem cell model of cortical interneuron (hcIN) development to elucidate its roles in this process. We identified genome-wide CHD2 binding profiles during hcIN differentiation, defining direct CHD2 targets related to neurogenesis in hcIN progenitors and to neuronal function in hcINs. CHD2 bound sites were frequently coenriched with histone H3 lysine 27 acetylation (H3K27ac) and associated with high gene expression, indicating roles for CHD2 in promoting gene expression during hcIN development. Binding sites for different classes of transcription factors were enriched at CHD2 bound regions during differentiation, suggesting transcription factors that may cooperatively regulate stage-specific gene expression with CHD2. We also demonstrated that CHD2 haploinsufficiency altered CHD2 and H3K27ac coenrichment on chromatin and expression of associated genes, decreasing acetylation and expression of cell cycle genes while increasing acetylation and expression of neuronal genes, to cause precocious differentiation. Together, these data describe CHD2 direct targets and mechanisms by which CHD2 prevents precocious hcIN differentiation, which are likely to be disrupted by pathogenic CHD2 mutation to cause neurodevelopmental disorders. © 2022, The Author(s).
Funding details
National Institutes of HealthNIHR01GM66815, R01MH124808
Office of Extramural Research, National Institutes of HealthOERR01NS114551
Children’s Discovery InstituteCDI
Office of Research Infrastructure Programs, National Institutes of HealthORIP, NIH, NIH-ORIP, ORIP
Clinical and Translational Science Institute, University of FloridaCTSIP50HD103525
Document Type: Article
Publication Stage: Final
Source: Scopus
Incisionless targeted adeno-associated viral vector delivery to the brain by focused ultrasound-mediated intranasal administration
(2022) eBioMedicine, 84, art. no. 104277, .
Ye, D.a , Yuan, J.a , Yang, Y.a , Yue, Y.a , Hu, Z.a , Fadera, S.a , Chen, H.a b
a Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO 63130, United States
b Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO 63108, United States
Abstract
Background: Adeno-associated viral (AAV) vectors are currently the leading platform for gene therapy with the potential to treat a variety of central nervous system (CNS) diseases. There are numerous methods for delivering AAVs to the CNS, such as direct intracranial injection (DI), intranasal delivery (IN), and intravenous injection with focused ultrasound-induced blood–brain barrier disruption (FUS-BBBD). However, non-invasive and efficient delivery of AAVs to the brain with minimal systemic toxicity remain the major challenge. This study aims to investigate the potential of focused ultrasound-mediated intranasal delivery (FUSIN) in AAV delivery to brain. Methods: Mice were intranasally administered with AAV5 encoding enhanced green fluorescence protein (AAV5-EGFP) followed by FUS sonication in the presence of systemically injected microbubbles. Mouse brains and other major organs were harvested for immunohistological staining, PCR quantification, and in situ hybridization. The AAV delivery outcomes were compared with those of DI, FUS-BBBD, and IN delivery. Findings: FUSIN achieved safe and efficient delivery of AAV5-EGFP to spatially targeted brain locations, including a superficial brain site (cortex) and a deep brain region (brainstem). FUSIN achieved comparable delivery outcomes as the established DI, and displayed 414.9-fold and 2073.7-fold higher delivery efficiency than FUS-BBBD and IN. FUSIN was associated with minimal biodistribution in peripheral organs, which was comparable to that of DI. Interpretation: Our results suggest that FUSIN is a promising technique for non-invasive, efficient, safe, and spatially targeted AAV delivery to the brain. Funding: National Institutes of Health (NIH) grants R01EB027223, R01EB030102, R01MH116981, and UG3MH126861. © 2022 The Author(s)
Author Keywords
Adeno-associated viral vectors; Blood–brain barrier; Focused ultrasound; Gene therapy; Intranasal delivery
Funding details
National Institutes of HealthNIHR01EB027223, R01EB030102, R01MH116981, UG3MH126861
Document Type: Article
Publication Stage: Final
Source: Scopus
Multidimensional analysis and therapeutic development using patient iPSC-derived disease models of Wolfram syndrome
(2022) JCI insight, 7 (18), .
Kitamura, R.A.a , Maxwell, K.G.a b , Ye, W.c , Kries, K.a , Brown, C.M.a , Augsornworawat, P.a b , Hirsch, Y.d , Johansson, M.M.d , Weiden, T.e , Ekstein, J.d , Cohen, J.f , Klee, J.f , Leslie, K.f , Simeonov, A.c , Henderson, M.J.c , Millman, J.R.a b , Urano, F.a g
a Department of Medicine, Division of Endocrinology, Metabolism, Lipid Research, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
b Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
c National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, MD, United States
d Committee for Prevention of Jewish Genetic Diseases, Brooklyn, NY, United States
e Committee for Prevention of Jewish Genetic DiseasesJerusalem, Israel
f Amylyx Pharmaceuticals Inc., Cambridge, MA, United States
g Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
Abstract
Wolfram syndrome is a rare genetic disorder largely caused by pathogenic variants in the WFS1 gene and manifested by diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Recent genetic and clinical findings have revealed Wolfram syndrome as a spectrum disorder. Therefore, a genotype-phenotype correlation analysis is needed for diagnosis and therapeutic development. Here, we focus on the WFS1 c.1672C>T, p.R558C variant, which is highly prevalent in the Ashkenazi Jewish population. Clinical investigation indicated that patients carrying the homozygous WFS1 c.1672C>T, p.R558C variant showed mild forms of Wolfram syndrome phenotypes. Expression of WFS1 p.R558C was more stable compared with the other known recessive pathogenic variants associated with Wolfram syndrome. Human induced pluripotent stem cell-derived (iPSC-derived) islets (SC-islets) homozygous for WFS1 c.1672C>T variant recapitulated genotype-related Wolfram syndrome phenotypes. Enhancing residual WFS1 function through a combination treatment of chemical chaperones mitigated detrimental effects caused by the WFS1 c.1672C>T, p.R558C variant and increased insulin secretion in SC-islets. Thus, the WFS1 c.1672C>T, p.R558C variant causes a mild form of Wolfram syndrome phenotypes, which can be remitted with a combination treatment of chemical chaperones. We demonstrate that our patient iPSC-derived disease model provides a valuable platform for further genotype-phenotype analysis and therapeutic development for Wolfram syndrome.
Author Keywords
Beta cells; Diabetes; Endocrinology; Genetic diseases; Genetics
Document Type: Article
Publication Stage: Final
Source: Scopus
Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS
(2022) The New England Journal of Medicine, 387 (12), pp. 1099-1110.
Miller, T.M., Cudkowicz, M.E., Genge, A., Shaw, P.J., Sobue, G., Bucelli, R.C., Chiò, A., Van Damme, P., Ludolph, A.C., Glass, J.D., Andrews, J.A., Babu, S., Benatar, M., McDermott, C.J., Cochrane, T., Chary, S., Chew, S., Zhu, H., Wu, F., Nestorov, I., Graham, D., Sun, P., McNeill, M., Fanning, L., Ferguson, T.A., Fradette, S., VALOR and OLE Working Group
From the Washington University School of Medicine, St. Louis (T.M.M., R.C.B.); the Sean M. Healey and AMG Center for ALS, Massachusetts General Hospital, Harvard Medical School, Boston (M.E.C., S.B.), and Biogen, Cambridge (T.C., S. Chary, S. Chew, H.Z., F.W., I.N., D.G., P.S., L.F., T.A.F., S.F.) – both in Massachusetts; Montreal Neurological Institute and Hospital, Montreal (A.G.); the Sheffield Institute for Translational Neuroscience, University of Sheffield, and the National Institute for Health and Care Research Sheffield Biomedical Research Centre and Clinical Research Facility, University of Sheffield and Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield (P.J.S., C.J.M.), and Biogen, Maidenhead (M.M.) – both in the United Kingdom; Aichi Medical University, Aichi, Japan (G.S.); the University of Turin, Turin, Italy (A.C.); KU Leuven, VIB Center for Brain and Disease Research, University Hospitals Leuven, Leuven, Belgium (P.V.D.); the University of Ulm, Ulm, and Deutsches Zentrum für Neurodegenerative Erkrankungen, Bonn – both in Germany (A.C.L.); Emory University, Atlanta (J.D.G.); the Neurological Institute, Columbia University Irving Medical Center, New York (J.A.A.); and the Department of Neurology, University of Miami, Miami (M.B.)
Abstract
BACKGROUND: The intrathecally administered antisense oligonucleotide tofersen reduces synthesis of the superoxide dismutase 1 (SOD1) protein and is being studied in patients with amyotrophic lateral sclerosis (ALS) associated with mutations in SOD1 (SOD1 ALS). METHODS: In this phase 3 trial, we randomly assigned adults with SOD1 ALS in a 2:1 ratio to receive eight doses of tofersen (100 mg) or placebo over a period of 24 weeks. The primary end point was the change from baseline to week 28 in the total score on the ALS Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) among participants predicted to have faster-progressing disease. Secondary end points included changes in the total concentration of SOD1 protein in cerebrospinal fluid (CSF), in the concentration of neurofilament light chains in plasma, in slow vital capacity, and in handheld dynamometry in 16 muscles. A combined analysis of the randomized component of the trial and its open-label extension at 52 weeks compared the results in participants who started tofersen at trial entry (early-start cohort) with those in participants who switched from placebo to the drug at week 28 (delayed-start cohort). RESULTS: A total of 72 participants received tofersen (39 predicted to have faster progression), and 36 received placebo (21 predicted to have faster progression). Tofersen led to greater reductions in concentrations of SOD1 in CSF and of neurofilament light chains in plasma than placebo. In the faster-progression subgroup (primary analysis), the change to week 28 in the ALSFRS-R score was -6.98 with tofersen and -8.14 with placebo (difference, 1.2 points; 95% confidence interval [CI], -3.2 to 5.5; P = 0.97). Results for secondary clinical end points did not differ significantly between the two groups. A total of 95 participants (88%) entered the open-label extension. At 52 weeks, the change in the ALSFRS-R score was -6.0 in the early-start cohort and -9.5 in the delayed-start cohort (difference, 3.5 points; 95% CI, 0.4 to 6.7); non-multiplicity-adjusted differences favoring early-start tofersen were seen for other end points. Lumbar puncture-related adverse events were common. Neurologic serious adverse events occurred in 7% of tofersen recipients. CONCLUSIONS: In persons with SOD1 ALS, tofersen reduced concentrations of SOD1 in CSF and of neurofilament light chains in plasma over 28 weeks but did not improve clinical end points and was associated with adverse events. The potential effects of earlier as compared with delayed initiation of tofersen are being further evaluated in the extension phase. (Funded by Biogen; VALOR and OLE ClinicalTrials.gov numbers, NCT02623699 and NCT03070119; EudraCT numbers, 2015-004098-33 and 2016-003225-41.). Copyright © 2022 Massachusetts Medical Society.
Document Type: Article
Publication Stage: Final
Source: Scopus
Laser stimulation of the skin for quantitative study of decision-making and motivation
(2022) Cell Reports Methods, 2 (9), art. no. 100296, .
Pai, J.a , Ogasawara, T.a , Bromberg-Martin, E.S.a , Ogasawara, K.a , Gereau, R.W.a b c d , Monosov, I.E.a b d e f
a Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
b Washington University Pain Center, Washington University, St. Louis, MO, United States
c Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Biomedical Engineering, Washington University, St. Louis, MO, United States
e Department of Neurosurgery, Washington University, St. Louis, MO, United States
f Department of Electrical Engineering, Washington University, St. Louis, MO, United States
Abstract
Neuroeconomics studies how decision-making is guided by the value of rewards and punishments. But to date, little is known about how noxious experiences impact decisions. A challenge is the lack of an aversive stimulus that is dynamically adjustable in intensity and location, readily usable over many trials in a single experimental session, and compatible with multiple ways to measure neuronal activity. We show that skin laser stimulation used in human studies of aversion can be used for this purpose in several key animal models. We then use laser stimulation to study how neurons in the orbitofrontal cortex (OFC), an area whose many roles include guiding decisions among different rewards, encode the value of rewards and punishments. We show that some OFC neurons integrated the positive value of rewards with the negative value of aversive laser stimulation, suggesting that the OFC can play a role in more complex choices than previously appreciated. © 2022 The Authors
Author Keywords
aversion; decision; motivation; neuroeconomics; orbitofrontal; value
Funding details
National Institute of Mental HealthNIMHMH106435, R01MH110594, R01MH116937
Army Research OfficeARO78259-NS-MUR
McKnight FoundationR01NS106953
University of WashingtonUW
Document Type: Article
Publication Stage: Final
Source: Scopus
Apolipoprotein E4 impairs the response of neurodegenerative retinal microglia and prevents neuronal loss in glaucoma
(2022) Immunity, 55 (9), pp. 1627-1644. Cited 1 time.
Margeta, M.A.a , Yin, Z.b , Madore, C.c , Pitts, K.M.a , Letcher, S.M.a , Tang, J.d , Jiang, S.e , Gauthier, C.D.b , Silveira, S.R.b , Schroeder, C.M.b , Lad, E.M.f , Proia, A.D.g , Tanzi, R.E.h , Holtzman, D.M.i , Krasemann, S.j , Chen, D.F.e , Butovsky, O.k
a Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
b Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
c Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; Univ. Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, F-33000 Bordeaux, France
d Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA; Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
e Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, United States
f Department of Ophthalmology, Duke University Medical Center, Durham, NC, United States
g Department of Pathology, Duke University Medical Center, Durham, NC, USA; Department of Pathology, Campbell University School of Osteopathic Medicine, Lillington, NC, USA
h Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, United States
i Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer Disease Research Center, Washington University, St. Louis, MO, United States
j Institute of Neuropathology, University Medical Center Hamburg-EppendorfHamburg, Germany
k Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; Evergrande Center for Immunologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
Abstract
The apolipoprotein E4 (APOE4) allele is associated with an increased risk of Alzheimer disease and a decreased risk of glaucoma, but the underlying mechanisms remain poorly understood. Here, we found that in two mouse glaucoma models, microglia transitioned to a neurodegenerative phenotype characterized by upregulation of Apoe and Lgals3 (Galectin-3), which were also upregulated in human glaucomatous retinas. Mice with targeted deletion of Apoe in microglia or carrying the human APOE4 allele were protected from retinal ganglion cell (RGC) loss, despite elevated intraocular pressure (IOP). Similarly to Apoe-/- retinal microglia, APOE4-expressing microglia did not upregulate neurodegeneration-associated genes, including Lgals3, following IOP elevation. Genetic and pharmacologic targeting of Galectin-3 ameliorated RGC degeneration, and Galectin-3 expression was attenuated in human APOE4 glaucoma samples. These results demonstrate that impaired activation of APOE4 microglia is protective in glaucoma and that the APOE-Galectin-3 signaling can be targeted to treat this blinding disease. Copyright © 2022 Elsevier Inc. All rights reserved.
Author Keywords
Alzheimer disease; APOE4; Galectin-3; glaucoma; Lgals3; microglia; neurodegeneration; neuroprotection; retina
Document Type: Article
Publication Stage: Final
Source: Scopus
Validation of blood-based transcriptomic circadian phenotyping in older adults
(2022) Sleep, 45 (9), .
Smith, S.K.a b , Tran, P.c , Madden, K.A.c , Boyd, J.c , Braun, R.d , Musiek, E.S.a b c e , Ju, Y.-E.S.a b c e
a Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
b Center on Biological Rhythms and Sleep (COBRAS), Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Molecular Biosciences, Northwestern University, Chicago, IL, United States
e Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
Document Type: Article
Publication Stage: Final
Source: Scopus
Binary acoustic metasurfaces for dynamic focusing of transcranial ultrasound
(2022) Frontiers in Neuroscience, 16, art. no. 984953, .
Hu, Z.a , Yang, Y.a , Xu, L.a , Hao, Y.b , Chen, H.a b
a Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO, United States
b Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO, United States
Abstract
Transcranial focused ultrasound (tFUS) is a promising technique for non-invasive and spatially targeted neuromodulation and treatment of brain diseases. Acoustic lenses were designed to correct the skull-induced beam aberration, but these designs could only generate static focused ultrasound beams inside the brain. Here, we designed and 3D printed binary acoustic metasurfaces (BAMs) for skull aberration correction and dynamic ultrasound beam focusing. BAMs were designed by binarizing the phase distribution at the surface of the metasurfaces. The phase distribution was calculated based on time reversal to correct the skull-induced phase aberration. The binarization enabled the ultrasound beam to be dynamically steered along wave propagation direction by adjusting the operation frequency of the incident ultrasound wave. The designed BAMs were manufactured by 3D printing with two coding bits, a polylactic acid unit for bit “1” and a water unit for bit “0.” BAMs for single- and multi-point focusing through the human skull were designed, 3D printed, and validated numerically and experimentally. The proposed BAMs with subwavelength scale in thickness are simple to design, easy to fabric, and capable of correcting skull aberration and achieving dynamic beam steering. Copyright © 2022 Hu, Yang, Xu, Hao and Chen.
Author Keywords
aberration correction; acoustic lens; beam steering; binary acoustic metasurface; dynamic focusing; FUS-BBBD; neuromodulation; transcranial focused ultrasound
Funding details
National Institutes of HealthNIHR01EB027223, R01EB030102, R01MH116981, UG3MH126861
Office of Naval ResearchONRN00014-19-1-2335
Document Type: Article
Publication Stage: Final
Source: Scopus
Multiscale photoacoustic tomography of neural activities with GCaMP calcium indicators
(2022) Journal of Biomedical Optics, 27 (9), .
Zhang, R.a , Li, L.S.b , Rao, B.a , Rong, H.a , Sun, M.-Y.c , Yao, J.a , Chen, R.d , Zhou, Q.d , Mennerick, S.c , Raman, B.a , Wang, L.V.b
a Washington University in Saint Louis, Department of Biomedical Engineering, Saint Louis, Missouri, United States, United States
b California Institute of Technology, Caltech Optical Imaging Laboratory, rew and Peggy Cherng Department of Medical Engineering, Department of Electrical Engineering, Pasadena, CA, United States
c Washington University School of Medicine, Department of Psychiatry, Saint Louis, Missouri, United States, United States
d University of Southern California, Department of Biomedical Engineering, Los Angeles, CA, United States
Abstract
SIGNIFICANCE: Optical imaging of responses in fluorescently labeled neurons has progressed significantly in recent years. However, there is still a need to monitor neural activities at divergent spatial scales and at depths beyond the optical diffusion limit. AIM: To meet these needs, we aim to develop multiscale photoacoustic tomography (PAT) to image neural activities across spatial scales with a genetically encoded calcium indicator GCaMP. APPROACH: First, using photoacoustic microscopy, we show that depth-resolved GCaMP signals can be monitored in vivo from a fly brain in response to odor stimulation without depth scanning and even with the cuticle intact. In vivo monitoring of GCaMP signals was also demonstrated in mouse brains. Next, using photoacoustic computed tomography, we imaged neural responses of a mouse brain slice at depths beyond the optical diffusion limit. RESULTS: We provide the first unambiguous demonstration that multiscale PAT can be used to record neural activities in transgenic flies and mice with select neurons expressing GCaMP. CONCLUSIONS: Our results indicate that the combination of multiscale PAT and fluorescent neural activity indicators provides a methodology for imaging targeted neurons at various scales.
Author Keywords
calcium indicators; GCaMP; neural imaging; photoacoustic tomography
Document Type: Article
Publication Stage: Final
Source: Scopus
Modeling Neonatal Intraventricular Hemorrhage through Intraventricular Injection of Hemoglobin
(2022) Journal of Visualized Experiments: JoVE, (186), .
Miller, B.A.a , Pan, S.b , Yang, P.H.b , Wang, C.c , Trout, A.L.c , DeFreitas, D.b , Ramagiri, S.b , Olson, S.D.d , Strahle, J.M.e
a Department of Neurosurgery, University of Kentucky; Department of Pediatric Surgery, University of Texas
b Department of Neurological Surgery, Washington University in St. Louis School of Medicine
c Department of Neurosurgery, University of Kentucky
d Department of Pediatric Surgery, University of Texas
e Department of Neurological Surgery, Washington University in St. Louis School of Medicine; Department of Orthopedic Surgery, Washington University in St. Louis School of Medicine; Department of Pediatrics, Washington University in St. Louis School of Medicine;
Abstract
Neonatal intraventricular hemorrhage (IVH) is a common consequence of premature birth and leads to brain injury, posthemorrhagic hydrocephalus (PHH), and lifelong neurological deficits. While PHH can be treated by temporary and permanent cerebrospinal fluid (CSF) diversion procedures (ventricular reservoir and ventriculoperitoneal shunt, respectively), there are no pharmacological strategies to prevent or treat IVH-induced brain injury and hydrocephalus. Animal models are needed to better understand the pathophysiology of IVH and test pharmacological treatments. While there are existing models of neonatal IVH, those that reliably result in hydrocephalus are often limited by the necessity for large-volume injections, which may complicate modeling of the pathology or introduce variability in the clinical phenotype observed. Recent clinical studies have implicated hemoglobin and ferritin in causing ventricular enlargement after IVH. Here, we develop a straightforward animal model that mimics the clinical phenotype of PHH utilizing small-volume intraventricular injections of the blood breakdown product hemoglobin. In addition to reliably inducing ventricular enlargement and hydrocephalus, this model results in white matter injury, inflammation, and immune cell infiltration in periventricular and white matter regions. This paper describes this clinically relevant, simple method for modeling IVH-PHH in neonatal rats using intraventricular injection and presents methods for quantifying ventricle size post injection.
Document Type: Article
Publication Stage: Final
Source: Scopus
Examining virtual driving test performance and its relationship to individuals with HIV-associated neurocognitive disorders
(2022) Frontiers in Neuroscience, 16, art. no. 912766, .
Grethlein, D.a b , Pirrone, V.c , Devlin, K.N.d , Dampier, W.c , Szep, Z.e , Winston, F.K.f g , Ontañón, S.b , Walshe, E.A.f , Malone, K.h , Tillman, S.h , Ances, B.M.i , Kandadai, V.a , Kolson, D.L.j , Wigdahl, B.c
a Diagnostic Driving, Inc, Philadelphia, PA, United States
b Department of Computer Science, The Games Artificial Intelligence and Media Systems (GAIMS) Center, College of Computing and Informatics, Drexel University, Philadelphia, PA, United States
c Department of Microbiology and Immunology, College of Medicine, Institute for Molecular Medicine and Infectious Disease, Drexel University, Philadelphia, PA, United States
d Applied Neuro-Technologies Lab, Department of Psychological and Brain Sciences, College of Arts and Sciences, Drexel University, Philadelphia, PA, United States
e Division of Infectious Diseases and HIV Medicine, Department Medicine, Partnership Comprehensive Care Practice, College of Medicine, Drexel University, Philadelphia, PA, United States
f Center for Injury Research and Prevention, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
g Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
h College of Medicine, Drexel University, Philadelphia, PA, United States
i Department of Neurology, Hope Center for Neurological Disorders, School of Medicine, Washington University, St. Louis, MO, United States
j Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
Abstract
Significance: Existing screening tools for HIV-associated neurocognitive disorders (HAND) are often clinically impractical for detecting milder forms of impairment. The formal diagnosis of HAND requires an assessment of both cognition and impairment in activities of daily living (ADL). To address the critical need for identifying patients who may have disability associated with HAND, we implemented a low-cost screening tool, the Virtual Driving Test (VDT) platform, in a vulnerable cohort of people with HIV (PWH). The VDT presents an opportunity to cost-effectively screen for milder forms of impairment while providing practical guidance for a cognitively demanding ADL. Objectives: We aimed to: (1) evaluate whether VDT performance variables were associated with a HAND diagnosis and if so; (2) systematically identify a manageable subset of variables for use in a future screening model for HAND. As a secondary objective, we examined the relative associations of identified variables with impairment within the individual domains used to diagnose HAND. Methods: In a cross-sectional design, 62 PWH were recruited from an established HIV cohort and completed a comprehensive neuropsychological assessment (CNPA), followed by a self-directed VDT. Dichotomized diagnoses of HAND-specific impairment and impairment within each of the seven CNPA domains were ascertained. A systematic variable selection process was used to reduce the large amount of VDT data generated, to a smaller subset of VDT variables, estimated to be associated with HAND. In addition, we examined associations between the identified variables and impairment within each of the CNPA domains. Results: More than half of the participants (N = 35) had a confirmed presence of HAND. A subset of twenty VDT performance variables was isolated and then ranked by the strength of its estimated associations with HAND. In addition, several variables within the final subset had statistically significant associations with impairment in motor function, executive function, and attention and working memory, consistent with previous research. Conclusion: We identified a subset of VDT performance variables that are associated with HAND and assess relevant functional abilities among individuals with HAND. Additional research is required to develop and validate a predictive HAND screening model incorporating this subset. Copyright © 2022 Grethlein, Pirrone, Devlin, Dampier, Szep, Winston, Ontañón, Walshe, Malone, Tillman, Ances, Kandadai, Kolson and Wigdahl.
Author Keywords
driving simulator; HIV-associated neurocognitive disorders; impairment detection; screening tool; variable selection
Funding details
National Institutes of HealthNIH
National Institute of Mental HealthNIMHP30MH092177, R43MH122035
Small Business Innovation ResearchSBIR
Document Type: Article
Publication Stage: Final
Source: Scopus
Analysis of neuronal injury transcriptional response identifies CTCF and YY1 as co-operating factors regulating axon regeneration
(2022) Frontiers in Molecular Neuroscience, 15, art. no. 967472, .
Avraham, O.a , Le, J.a , Leahy, K.a , Li, T.b c , Zhao, G.a d , Cavalli, V.a c e
a Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
b Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
c Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, United States
d Department of Pathology and Immunology, 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
Abstract
Injured sensory neurons activate a transcriptional program necessary for robust axon regeneration and eventual target reinnervation. Understanding the transcriptional regulators that govern this axon regenerative response may guide therapeutic strategies to promote axon regeneration in the injured nervous system. Here, we used cultured dorsal root ganglia neurons to identify pro-regenerative transcription factors. Using RNA sequencing, we first characterized this neuronal culture and determined that embryonic day 13.5 DRG (eDRG) neurons cultured for 7 days are similar to e15.5 DRG neurons in vivo and that all neuronal subtypes are represented. This eDRG neuronal culture does not contain other non-neuronal cell types. Next, we performed RNA sequencing at different time points after in vitro axotomy. Analysis of differentially expressed genes revealed upregulation of known regeneration associated transcription factors, including Jun, Atf3 and Rest, paralleling the axon injury response in vivo. Analysis of transcription factor binding sites in differentially expressed genes revealed other known transcription factors promoting axon regeneration, such as Myc, Hif1α, Pparγ, Ascl1a, Srf, and Ctcf, as well as other transcription factors not yet characterized in axon regeneration. We next tested if overexpression of novel candidate transcription factors alone or in combination promotes axon regeneration in vitro. Our results demonstrate that expression of Ctcf with Yy1 or E2f2 enhances in vitro axon regeneration. Our analysis highlights that transcription factor interaction and chromatin architecture play important roles as a regulator of axon regeneration. Copyright © 2022 Avraham, Le, Leahy, Li, Zhao and Cavalli.
Author Keywords
axon regeneration; bioinformatics analyses; CTCF; dorsal root ganglia; E2F2; sensory neurons; transcription factors; YY1
Funding details
National Institutes of HealthNIHR01 NS096034, R35 NS122260
Center of Regenerative Medicine, Washington University in St. LouisCRM, WUSTL
Document Type: Article
Publication Stage: Final
Source: Scopus
Enhancing neuroimaging genetics through meta-analysis for Tourette syndrome (ENIGMA-TS): A worldwide platform for collaboration
(2022) Frontiers in Psychiatry, 13, art. no. 958688, .
Paschou, P.a , Jin, Y.a , Müller-Vahl, K.b , Möller, H.E.c , Rizzo, R.d , Hoekstra, P.J.e , Roessner, V.f , Mol Debes, N.g , Worbe, Y.h , Hartmann, A.i , Mir, P.j k , Cath, D.e , Neuner, I.l m n , Eichele, H.o , Zhang, C.p , Lewandowska, K.q , Munchau, A.r , Verrel, J.r , Musil, R.s , Silk, T.J.t , Hanlon, C.A.u , Bihun, E.D.v , Brandt, V.w , Dietrich, A.e , Forde, N.x , Ganos, C.y , Greene, D.J.z , Chu, C.p , Grothe, M.J.j k , Hershey, T.v , Janik, P.aa , Koller, J.M.v , Martin-Rodriguez, J.F.j k , Müller, K.c , Palmucci, S.d , Prato, A.ab , Ramkiran, S.l m n , Saia, F.ac , Szejko, N.aa , Torrecuso, R.c , Tumer, Z.ad ae , Uhlmann, A.f , Veselinovic, T.l , Wolańczyk, T.af , Zouki, J.-J.t , Jain, P.a , Topaloudi, A.a , Kaka, M.a , Yang, Z.a , Drineas, P.ag , Thomopoulos, S.I.ah , White, T.ai , Veltman, D.J.aj , Schmaal, L.ak , Stein, D.J.al , Buitelaar, J.x , Franke, B.x , van den Heuvel, O.am , Jahanshad, N.ah , Thompson, P.M.ah , Black, K.J.v , the ENIGMA-TS Working Groupan
a Department of Biological Sciences, Purdue University, West Lafayette, IN, United States
b Department of Psychiatry, Hannover University Medical School, Hannover, Germany
c Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
d Radiology Unit 1, Department of Medical Surgical Sciences and Advanced Technologies, University of Catania, Catania, Italy
e University Medical Center Groningen, Department of Psychiatry, University of Groningen, Groningen, Netherlands
f Department of Child and Adolescent Psychiatry, Technische Universität (TU) Dresden, Dresden, Germany
g Department of Pediatrics, Herlev University Hospital, Herlev, Denmark
h Department of Neurophysiology, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France
i Pitié-Salpêtrière Hospital, Paris, France
j Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC, University of Seville, Seville, Spain
k Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
l Department of Psychiatry, Psychotherapy and Psychosomatic, RWTH Aachen University, Aachen, Germany
m Institute of Neuroscience and Medicine 4, Forschungszentrum Jülich GmbH, Jülich, Germany
n JARA BRAIN—Translational Medicine, Aachen, Germany
o Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway
p Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai, China
q Department of Psychiatry, Medical University of Warsaw, Warsaw, Poland
r Institute of Systems Motor Science, University of Lübeck, Lübeck, Germany
s Department of Psychiatry and Psychotherapy, Ludwig Maximilians University of Munich, Munich, Germany
t Deakin University, Geelong, VIC, Australia
u Wake Forest School of Medicine, Winston-Salem, NC, United States
v Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
w Centre for Innovation in Mental Health, School of Psychology, University of Southampton, Southampton, United Kingdom
x Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands
y Department of Neurology, Charité-University Medicine Berlin, Berlin, Germany
z Department of Cognitive Science, University of California, San Diego, La Jolla, CA, United States
aa Department of Neurology, Medical University of Warsaw, Warsaw, Poland
ab Child and Adolescent Neurology and Psychiatric Section, Department of Clinical and Experimental Medicine, Catania University, Catania, Italy
ac Child Neuropsychiatry Unit, Department of Clinical and Experimental Medicine, School of Medicine, University of Catania, Catania, Italy
ad Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
ae Department of Clinical Genetics, Kennedy Center, Copenhagen University Hospital Rigshospitalet, Glostrup, Denmark
af Department of Child Psychiatry, Medical University of Warsaw, Warsaw, Poland
ag Department of Computer Science, Purdue University, West Lafayette, IN, United States
ah Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
ai Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC–Sophia Children’s Hospital, University Medical Center Rotterdam, Rotterdam, Netherlands
aj Department of Psychiatry, Amsterdam Neuroscience, Amsterdam UMC, Amsterdam, Netherlands
ak Centre for Youth Mental Health, University of Melbourne, Melbourne, VIC, Australia
al South African Medical Research Council (SAMRC) Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, South Africa
am Department Psychiatry, Department Anatomy and Neuroscience, Amsterdam University Medical Center (UMC), Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands
Abstract
Tourette syndrome (TS) is characterized by multiple motor and vocal tics, and high-comorbidity rates with other neuropsychiatric disorders. Obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), major depressive disorder (MDD), and anxiety disorders (AXDs) are among the most prevalent TS comorbidities. To date, studies on TS brain structure and function have been limited in size with efforts mostly fragmented. This leads to low-statistical power, discordant results due to differences in approaches, and hinders the ability to stratify patients according to clinical parameters and investigate comorbidity patterns. Here, we present the scientific premise, perspectives, and key goals that have motivated the establishment of the Enhancing Neuroimaging Genetics through Meta-Analysis for TS (ENIGMA-TS) working group. The ENIGMA-TS working group is an international collaborative effort bringing together a large network of investigators who aim to understand brain structure and function in TS and dissect the underlying neurobiology that leads to observed comorbidity patterns and clinical heterogeneity. Previously collected TS neuroimaging data will be analyzed jointly and integrated with TS genomic data, as well as equivalently large and already existing studies of highly comorbid OCD, ADHD, ASD, MDD, and AXD. Our work highlights the power of collaborative efforts and transdiagnostic approaches, and points to the existence of different TS subtypes. ENIGMA-TS will offer large-scale, high-powered studies that will lead to important insights toward understanding brain structure and function and genetic effects in TS and related disorders, and the identification of biomarkers that could help inform improved clinical practice. Copyright © 2022 Paschou, Jin, Müller-Vahl, Möller, Rizzo, Hoekstra, Roessner, Mol Debes, Worbe, Hartmann, Mir, Cath, Neuner, Eichele, Zhang, Lewandowska, Munchau, Verrel, Musil, Silk, Hanlon, Bihun, Brandt, Dietrich, Forde, Ganos, Greene, Chu, Grothe, Hershey, Janik, Koller, Martin-Rodriguez, Müller, Palmucci, Prato, Ramkiran, Saia, Szejko, Torrecuso, Tumer, Uhlmann, Veselinovic, Wolańczyk, Zouki, Jain, Topaloudi, Kaka, Yang, Drineas, Thomopoulos, White, Veltman, Schmaal, Stein, Buitelaar, Franke, van den Heuvel, Jahanshad, Thompson and Black.
Author Keywords
brain MRI; ENIGMA; genetics; neuroimaging; Tourette syndrome
Funding details
National Science FoundationNSF1715202
National Institutes of HealthNIHK01MH104592, P41EB015922, R01MH116147, R01MH118217
National Institute of Mental HealthNIMHR01MH126213
Dagmar Marshalls Fond
Universidad de SevillaUSE-18817-A
Innovative Medicines InitiativeIMI777394
Document Type: Article
Publication Stage: Final
Source: Scopus
Association of Mental Health Burden with Prenatal Cannabis Exposure from Childhood to Early Adolescence: Longitudinal Findings from the Adolescent Brain Cognitive Development (ABCD) Study
(2022) JAMA Pediatrics, .
Baranger, D.A.A.a , Paul, S.E.a , Colbert, S.M.C.b , Karcher, N.R.b , Johnson, E.C.b , Hatoum, A.S.b , Bogdan, R.a
a Department of Psychological and Brain Sciences, Washington University in St Louis, St Louis, MO, United States
b Department of Psychiatry, Washington University School of Medicine in St Louis, St Louis, MO, United States
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
MRI-guided laser interstitial thermal therapy for deep-seated gliomas in children with neurofibromatosis type 1: report of two cases
(2022) Child’s Nervous System, .
Cross, K.A.a , Salehi, A.b , Abdelbaki, M.S.c , Gutmann, D.H.d , Limbrick, D.D., Jr.e
a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
b Division of Pediatric Neurosurgery, Department of Neurological Surgery, University of Nebraska Medical Center, Omaha Children’s Hospital Medical Center, Omaha, NE, United States
c Division of Hematology and Oncology, Department of Pediatrics, St. Louis Children’s Hospital, 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 Division of Pediatric Neurosurgery, Department of Neurological Surgery, St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Purpose: Nearly a quarter of neurofibromatosis type 1 (NF 1)- associated diencephalic low-grade tumors are refractory to chemotherapy. Addition of alternative treatment options with laser interstitial thermal therapy will have a positive impact on the outcome of these patients. Methods: We report on two illustrated cases of pediatric NF1- associated, chemoresistant, WHO grade 1 pilocytic astrocytomas treated with laser interstitial thermal therapy (LITT). Results: Both tumors responded favorably to LITT. Conclusion: LITT should be considered as a treatment option for chemoresistant deep-seated NF1-associated low-grade gliomas. © 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Author Keywords
Deep-seated gliomas; Laser interstitial thermal therapy; Neurofibromatosis type 1; Thalamic tumors
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Genome-wide meta-analysis for Alzheimer’s disease cerebrospinal fluid biomarkers
(2022) Acta Neuropathologica, .
Jansen, I.E.a b c , van der Lee, S.J.a b d , Gomez-Fonseca, D.e f g , de Rojas, I.h i , Dalmasso, M.C.j k , Grenier-Boley, B.l , Zettergren, A.m , Mishra, A.n , Ali, M.e f g , Andrade, V.j o , Bellenguez, C.l , Kleineidam, L.j o p , Küçükali, F.q r , Sung, Y.J.e f g , Tesí, N.a b d , Vromen, E.M.a b , Wightman, D.P.c , Alcolea, D.i s , Alegret, M.h i , Alvarez, I.t u , Amouyel, P.l , Athanasiu, L.v , Bahrami, S.v , Bailly, H.w , Belbin, O.i s , Bergh, S.x y , Bertram, L.z , Biessels, G.J.aa , Blennow, K.ab ac , Blesa, R.i s , Boada, M.h i , Boland, A.ad , Buerger, K.ae af , Carracedo, Á.ag ah , Cervera-Carles, L.i s , Chene, G.n ai , Claassen, J.A.H.R.aj ak , Debette, S.n ai al , Deleuze, J.-F.ad , de Deyn, P.P.am , Diehl-Schmid, J.an ao , Djurovic, S.ap aq , Dols-Icardo, O.i s , Dufouil, C.n ar , Duron, E.as , Düzel, E.at au , Fladby, T.av aw , Fortea, J.i s , Frölich, L.ax , García-González, P.h i , Garcia-Martinez, M.ay , Giegling, I.az , Goldhardt, O.an , Gobom, J.ac , Grimmer, T.an , Haapasalo, A.ba , Hampel, H.bb bc , Hanon, O.w bd , Hausner, L.ax , Heilmann-Heimbach, S.be , Helisalmi, S.bf , Heneka, M.T.o p , Hernández, I.h i , Herukka, S.-K.bg , Holstege, H.a b d , Jarholm, J.bh , Kern, S.m bi , Knapskog, A.-B.bj , Koivisto, A.M.bg bk bl , Kornhuber, J.bm , Kuulasmaa, T.bn , Lage, C.ay bo , Laske, C.bp bq , Leinonen, V.br bs , Lewczuk, P.bm bt , Lleó, A.i s , de Munain, A.L.i bu bv bw , Lopez-Garcia, S.ay , Maier, W.o , Marquié, M.h i , Mol, M.O.bz , Montrreal, L.h , Moreno, F.i bu bv , Moreno-Grau, S.h i , Nicolas, G.by , Nöthen, M.M.be , Orellana, A.h i , Pålhaugen, L.av aw , Papma, J.M.bz , Pasquier, F.l , Perneczky, R.ae ca cb cc , Peters, O.at cd , Pijnenburg, Y.A.L.a b , Popp, J.ce cf , Posthuma, D.c , Pozueta, A.ay , Priller, J.cd cg ch , Puerta, R.h , Quintela, I.ag , Ramakers, I.ci , Rodriguez-Rodriguez, E.ay , Rujescu, D.az , Saltvedt, I.cj ck , Sanchez-Juan, P.cl , Scheltens, P.a b , Scherbaum, N.cm , Schmid, M.cn , Schneider, A.o p , Selbæk, G.y av bj , Selnes, P.aw , Shadrin, A.v , Skoog, I.m bi , Soininen, H.bg , Tárraga, L.h i , Teipel, S.co cp , Tijms, B.a b , Tsolaki, M.cq , Van Broeckhoven, C.r cr , Van Dongen, J.q r , van Swieten, J.C.bz , Vandenberghe, R.cs ct , Vidal, J.-S.w , Visser, P.J.a b cu cv , Vogelgsang, J.cw cx , Waern, M.m cy , Wagner, M.o p , Wiltfang, J.cw cz da , Wittens, M.M.J.r db , Zetterberg, H.ab ac dc dd de , Zulaica, M.i bu bv , van Duijn, C.M.bx df , Bjerke, M.r db dg , Engelborghs, S.r db dg dh , Jessen, F.p di dj , Teunissen, C.E.b dk , Pastor, P.dl , Hiltunen, M.dm , Ingelsson, M.dn do dp , Andreassen, O.A.v dq , Clarimón, J.i s , Sleegers, K.q r , Ruiz, A.h i , Ramirez, A.j o p dj dr , Cruchaga, C.e f g , Lambert, J.-C.l , van der Flier, W.a b , EADB consortiumds , The GR@ACE study groupds
a Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC Location VUmc, Amsterdam, Netherlands
b Amsterdam Neuroscience, Neurodegeneration, Amsterdam, Netherlands
c Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU Amsterdam, Amsterdam, Netherlands
d Section Genomics of Neurodegenerative Diseases and Aging, Human Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, Netherlands
e Department of Psychiatry, 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 Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO, United States
h Research Center and Memory Clinic, Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain
i CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain
j Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
k Neurosciences and Complex Systems Unit (ENyS), CONICET, Hospital El Cruce, National University A. Jauretche (UNAJ), Florencio Varela, Argentina
l Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 – RID-AGE / Labex DISTALZ – Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, F-59000, France
m Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, Centre for Ageing and Health (AGECAP) at the University of Gothenburg, Gothenburg, Sweden
n University of Bordeaux, Inserm, Bordeaux Population Health Research Center, Team VINTAGE, UMR 1219, Bordeaux, 33000, France
o Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Medical Faculty, Bonn, Germany
p German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
q Complex Genetics of Alzheimer’s Disease Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium
r Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
s Sant Pau Memory Unit, Department of Neurology, Institut d’Investigacions Biomèdiques Sant Pau – Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
t Memory Disorders Unit, Department of Neurology, Hospital Universitari Mutua de Terrassa, Terrassa, Spain
u Fundació per a la Recerca Biomèdica i Social Mútua de Terrassa, Terrassa, Spain
v NORMENT Centre, Institute of Clinical Medicine, University of Oslo and Division of Mental Health, Oslo, Norway
w Université Paris Cité, EA4468, Maladie d’Alzheimer, F-75013 Paris, France
x The Research-Centre for Age-Related Functional Decline and Disease, Innlandet Hospital Trust, Brumunddal, Norway
y Norwegian National Centre for Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway
z Lübeck Interdisciplinary Platform for Genome Analytics, University of Lübeck, Lübeck, Germany
aa Department of Neurology, UMC Utrecht Brain Center, Utrecht, Netherlands
ab Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
ac Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
ad Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, Evry, 91057, France
ae German Center for Neurodegenerative Diseases (DZNE, Munich), Munich, Germany
af Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany
ag Grupo de Medicina Xenómica, Centro Nacional de Genotipado (CEGEN-PRB3-ISCIII), Universidade de Santiago de Compostela, Santiago de Compostela, Spain
ah Fundación Pública Galega de Medicina Xenómica-CIBERER-IDIS, Santiago de Compostela, Spain
ai Department of Neurology, CHU de Bordeaux, Bordeaux, 33000, France
aj Radboudumc Alzheimer Center, Department of Geriatrics, Radboud University Medical Center, Nijmegen, Netherlands
ak Donders Center for Medical Neuroscience, Nijmegen, Netherlands
al Department of Neurology, Boston University School of Medicine, Boston, MA 2115, United States
am Department of Neurology and Alzheimer Center Groningen, University Medical Center Groningen, Groningen, Netherlands
an Center for Cognitive Disorders, Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
ao kbo-Inn-Salzach-Hospital, Wasserburg am Inn, Germany
ap Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
aq Department of Clinical Science, NORMENT Centre, University of Bergen, Bergen, Norway
ar Pôle de Santé Publique Centre Hospitalier Universitaire (CHU) de Bordeaux, Bordeaux, France
as Univerisité Paris-Saclay. Inserm 1178 MOODS, Paris, France
at German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany
au Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, Magdeburg, Germany
av Institute of Clinical Medicine, University of Oslo, Oslo, Norway
aw Department of Neurology, Akershus University Hospital, Lorenskog, Norway
ax Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg, Germany
ay Cognitive Impairment Unit, Neurology Service, “Marqués de Valdecilla” University Hospital, Institute for Research “Marques de Valdecilla” (IDIVAL), University of Cantabria, Santander, Spain, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
az Division of General Psychiatry, Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria
ba A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
bb Alzheimer Precision Medicine (APM), Sorbonne University, AP-HP, Pitié-Salpêtrière Hospital, Paris, France
bc Neurology Business Group, Eisai Inc, 100 Tice Blvd, Woodcliff Lake, NJ 07677, United States
bd Service gériatrie, Centre Mémoire de Ressources et Recherches Ile de France-Broca, AP-HP, Hôpital Broca, Paris, F-75013, France
be Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, 53127, Germany
bf Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland
bg Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
bh Department of Neurology, Akershus University Hospital, Lorenskog, Norway
bi Region Västra Götaland, Sahlgrenska University Hospital, Psychiatry, Cognition and Old Age Psychiatry Clinic, Gothenburg, Sweden
bj Department of Geriatric Medicine, Oslo University Hospital, Oslo, Norway
bk Department of Neurology, Kuopio University Hospital, Kuopio, Finland
bl Department of Neurology, Helsinki University Hospital, Helsinki, Finland
bm Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen, and Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
bn Bioinformatics Center, Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
bo Atlantic Fellow at the Global Brain Health Institute (GBHI) -, University of California, San Francisco, United States
bp German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
bq Section for Dementia Research, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany
br Institute of Clinical Medicine, Neurosurgery, University of Eastern Finland, Kuopio, Finland
bs Department of Neurosurgery, Kuopio University Hospital, Kuopio, Finland
bt Department of Neurodegeneration Diagnostics, Medical University of Białystok, Białystok, Poland
bu Hospital Universitario Donostia-OSAKIDETZA, Donostia, Spain
bv Instituto Biodonostia, San Sebastián, Spain
bw University of The Basque Country, San Sebastian, Spain
bx Department of Epidemiology, ErasmusMC, Rotterdam, Netherlands
by Department of Genetics and CNR-MAJ, Normandie Univ, UNIROUEN, Inserm U1245 and CHU Rouen, Rouen, France
bz Department of Neurology and Alzheimer Center Erasmus MC, Erasmus MC University Medical Center, Rotterdam, Netherlands
ca Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany
cb Munich Cluster for Systems Neurology (SyNergy) Munich, Munich, Germany
cc Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, London, United Kingdom
cd German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany
ce Department of Geriatric Psychiatry, University Hospital of Psychiatry Zürich and University of Zürich, Zurich, Switzerland
cf Old Age Psychiatry, Department of Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland
cg Department of Psychiatry and Psychotherapy, Charité, Charitéplatz 1, Berlin, 10117, Germany
ch Department of Psychiatry and Psychotherapy, Klinikum rechts der isar, Technical University Munich, Munich, 81675, Germany
ci Department of Psychiatry and Neuropsychologie, Alzheimer Center Limburg, Maastricht University, Maastricht, Netherlands
cj Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
ck Department of Geriatrics, St Olav Hospital, University Hospital of Trondheim, Trondheim, Norway
cl Alzheimer’s Centre Reina Sofia-CIEN Foundation-ISCIII, Madrid, 28031, Spain
cm Department of Psychiatry and Psychotherapy, Medical Faculty, LVR-Hospital Essen, University of Duisburg-Essen, Essen, Germany
cn Institute of Medical Biometry, Informatics and Epidemiology, University Hospital of Bonn, Bonn, Germany
co German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany
cp Department of Psychosomatic Medicine, Rostock University Medical Center, Gehlsheimer Str. 20, Rostock, 18147, Germany
cq 1st Department of Neurology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Makedonia, Thessaloniki, Greece
cr Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium
cs Neurology, University Hospitals Leuven, Leuven, Belgium
ct Laboratory for Cognitive Neurology, Department of Neurosciences, Leuven Brain Institute, Leuven, Belgium
cu Alzheimer Center Limburg, School for Mental Health and Neuroscience Maastricht University, Maastricht, Netherlands
cv Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics Karolinska Institutet, Stockholm, Sweden
cw Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, Göttingen, Germany
cx Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, United States
cy Region Västra Götaland, Sahlgrenska University Hospital, Psychiatry, Psychosis Clinic, Gothenburg, Sweden
cz German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
da Medical Science Department, iBiMED, Aveiro, Portugal
db Center for Neurosciences (C4N), Vrije Universiteit Brussel, Brussels, Belgium
dc Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom
dd UK Dementia Research Institute at UCL, London, United Kingdom
de Hong Kong Center for Neurodegenerative Diseases, Hong Kong
df Nuffield Department of Population Health, Oxford University, Oxford, United Kingdom
dg Laboratory of Neurochemistry, Universitair Ziekenhuis Brussel, Brussels, Belgium
dh Department of Neurology, Universitair Ziekenhuis Brussel, Brussels, Belgium
di Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
dj Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
dk Neurochemistry Lab, Department of Clinical Chemistry, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands
dl Unit of Neurodegenerative diseases, Department of Neurology, University Hospital Germans Trias i Pujol and The Germans Trias i Pujol Research Institute (IGTP) Badalona, Barcelona, Spain
dm Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
dn Department of Public Health and Caring Sciences, Molecular Geriatrics, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
do Krembil Brain Institute, University Health Network, Toronto, ON, Canada
dp Department of Medicine and Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada
dq Addiction, Oslo University Hospital, Oslo, 0407, Norway
dr Department of Psychiatry, Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, San Antonio, TX, United States
Abstract
Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer’s disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume. © 2022, The Author(s).
Author Keywords
Alzheimer’s disease; Amyloid-beta; Cerebrospinal fluid; GWAS; Tau
Funding details
Fondation pour la Recherche sur Alzheimer
Alzheimer’s AssociationAAZEN-21-848495
JPND2019-466-236
Deutsche ForschungsgemeinschaftDFGRA 1971/8-1, RA 1971/6-1, RA1971/7-1
ALF 716681
European Regional Development FundERDF
Academy of FinlandAKA338182
Chan Zuckerberg InitiativeCZI
PI17/01474, 115975, PI19/01301, 115985, PI19/01240, PI16/01861, PI13/02434
2020-04-13, 2021-04-17
Bundesministerium für Bildung und ForschungBMBF
H2020 Marie Skłodowska-Curie ActionsMSCA860197
VetenskapsrådetVR11267, 2013-8717, 2019-01096, 2017-00639, 2015-02830, 825-2012-5041
AlzheimerfondenAF-939988, AF-646061, AF-741361, AF-930582
Nederlandse Organisatie voor Wetenschappelijk OnderzoekNWO024.004.012
FO2016-0214, FO2018-0214, FO2019- 0163
UK Dementia Research InstituteUK DRI2017-0243, 2017-00915, -201809-2016615, -742881
National Institutes of HealthNIHRF1AG058501, U01AG058922, R01AG064614, RF1AG053303, R01AG044546, R01AG064877, R01AG058501
National Institutes of HealthNIH1R01AG068398-01
Forskningsrådet om Hälsa, Arbetsliv och VälfärdFORTE2004-0145, 2008-1229, 2006-0596, 2001-2849, 2005-0762, 2013-1202, 2013-2300, 2001-2835, 2010-0870, 2001-2646, 2013-2496, 2008-1111, 2006-0020, 2004-0150, 2008-1210, 2003-0234, 2012-1138
Fonds Wetenschappelijk OnderzoekFWO
01G10102, 01GI0420, 04GI0434, 01GI0711, 01GI0423, 01GI0431, 01GI0422, 01GI0433, 01GI0429
Alzheimer’s AssociationAA2019-02075, IIRG-00-2159, AF-737641, AF-939825, IIRG-09-131338, ZEN-01-3151, ALFGBG-81392, IIRG-03-6168, AF-842471, 2016-01590, ALF GBG-771071
-715986
Centro de Investigación Biomédica en Red sobre Enfermedades NeurodegenerativasCIBERNED
Universiteit Antwerpen
Horizon 2020 Framework ProgrammeH2020
EU Joint Programme – Neurodegenerative Disease ResearchJPND301220
Deutsche ForschungsgemeinschaftDFG
Instituto de Salud Carlos IIIISCIII
European Regional Development FundERDFP30AG066444, P01AG003991, FI20/00215
Bundesministerium für Bildung und ForschungBMBF01ED1619A
Bijzonder Onderzoeksfonds UGentBOFPI12/02288, PI08/0139, PI16/01652, PI11/03028, PI20/01011
ALFGBG-720931
Alzheimer’s Drug Discovery FoundationADDF201809-2016862
Hope Center for Neurological Disorders
European Research CouncilERC2018-02532, ERC-2018-AdG GWAS2FUNC 834057, 681712
Fonds Wetenschappelijk OnderzoekFWO
Siemens Healthineers
Novartis
Eisai
Pfizer
Eisai
Eli Lilly and Company
Health~HollandLSH
Roche
20106
Eli Lilly and Company
Biogen
Servier
ZonMw
Nederlandse Organisatie voor Wetenschappelijk OnderzoekNWO
Seventh Framework ProgrammeFP7
GE Healthcare
Document Type: Article
Publication Stage: Article in Press
Source: Scopus